3-(Carboxymethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

ABSTRACT

The invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

This application is a continuation of U.S. Non-Provisional patent application Ser. No. 17/188,884, filed Mar. 1, 2021, which is a continuation of U.S. Non-Provisional patent application Ser. No. 17/007,557, filed Aug. 31, 2020, now abandoned, which is a continuation of U.S. Non-Provisional patent application Ser. No. 16/454,489, filed Jun. 27, 2019, now U.S. Pat. No. 10,807,989, which is a continuation of U.S. Non-Provisional patent application Ser. No. 16/212,723, filed Dec. 7, 2018, abandoned, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/980,181, filed May 15, 2018, abandoned, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/405,919, filed Jan. 13, 2017, abandoned, which claims foreign priority of European Patent Application No. 16 151 014.4, filed Jan. 13, 2016, the disclosures of which are incorporated herein by reference.

The invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body. The opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors. After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.

Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects. The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results from preclinical experiments suggest that NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treat moderate to severe acute and chronic pain. However, the therapeutic window of strong opioids is limited by severe side effects such as nausea and vomiting, constipation, dizziness, somnolence, respiratory depression, physical dependence and abuse. Furthermore, it is known that MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strong opioids are mediated by activation of classic opioid-receptors within the central nervous system. Furthermore, peripheral opioid receptors, when activated, can inhibit transmission of nociceptive signals shown in both, clinical and animal studies (Gupta et al., 2001; Kalso et al., 2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemic administration, one approach has been to provide peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039). Such peripherally acting compounds might combine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with both the NOP receptor and the MOP receptor. Such compounds have for instance been described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.

On the one hand, it would be desirable to provide analgesics that selectively act on the NOP receptor system but less pronounced on the classic opioid receptor system, especially MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity. On the other hand, it would be desirable to provide analgesics that act on the NOP receptor system and also to a balanced degree on the MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity.

There is a need for medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art. Where possible, such medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically active compounds, preferably analgesics that have advantages compared to the prior art.

This object has been achieved by the subject-matter of the patent claims.

A first aspect of the invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I) wherein

R¹ and R² independently of one another mean

-   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein     said 3-12-membered cycloalkyl moiety is optionally connected through     —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,     unsubstituted; or -   a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein     said 3-12-membered heterocycloalkyl moiety is optionally connected     through —C₁-C₆-alkylene-, linear or branched, saturated or     unsaturated, unsubstituted; -   or -   R¹ and R² together with the nitrogen atom to which they are attached     form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or     —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl,     linear or branched, saturated or unsaturated, unsubstituted or     substituted with one, two, three or four substituents independently     of one another selected from the group consisting of —F, —Cl, —Br     and —I; -   preferably with the proviso that R¹ and R² do not simultaneously     mean —H; -   R³ means -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,     linear or branched, saturated or unsaturated, unsubstituted, mono-     or polysubstituted;

a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;

-   a 6-14-membered aryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 6 membered aryl moiety is optionally     connected through —C₁-C₆-alkylene-, linear or branched, saturated or     unsaturated, unsubstituted, mono- or polysubstituted; or -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 5-14-membered heteroaryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted; -   R⁴ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl     is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—;

a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;

-   a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     heterocycloalkyl moiety is optionally connected through     —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; or wherein said     3-12-membered heterocycloalkyl moiety is optionally connected     through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; -   a 6-14-membered aryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 6-14-membered aryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted;     or wherein said 6-14-membered aryl moiety is optionally connected     through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or     5-14-membered heteroaryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 5 membered heteroaryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted;     or wherein said 5-14-membered heteroaryl moiety is optionally     connected through —C(═O)—, —(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; -   X means —O—, —S— or —NR⁶—; -   R⁵ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,     linear or branched, saturated or unsaturated, unsubstituted, mono-     or polysubstituted; -   a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     heterocycloalkyl moiety is optionally connected through     —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   a 6-14-membered aryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 6-14-membered aryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted;     or -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 5-14-membered heteroaryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted; -   in case X means NR⁶, R⁶ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,     linear or branched, saturated or unsaturated, unsubstituted, mono-     or polysubstituted; -   a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; wherein said 3-12-membered     heterocycloalkyl moiety is optionally connected through     —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   a 6-14-membered aryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 6-14-membered aryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted;     or -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 5-14-membered heteroaryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted, mono- or polysubstituted; -   or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to     which they are attached form a 3-12-membered heterocycloalkyl     moiety, saturated or unsaturated, unsubstituted, mono- or     polysubstituted; -   R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰     independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or     —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted, mono- or polysubstituted; -   wherein “mono- or polysubstituted” means that one or more hydrogen     atoms are replaced by a substituent independently of one another     selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R²¹,     —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H,     —O—(CH₂CH₂—O—)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹,     —OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²²,     —NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²²,     —NR²¹C(═O)R²², —NR²¹C(═O)—OR²², —NR₂₃C(═O)NR₂₁R₂₂, —NR₂₁S(═O)₂R₂₂,     —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²;     wherein -   R²¹, R²² and R²³ independently of one another mean -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl; -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,     unsubstituted; wherein said 3-12-membered cycloalkyl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted or substituted with one,     two, three or four substituents independently of one another     selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,     —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; -   a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,     unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted or substituted with one,     two, three or four substituents independently of one another     selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,     —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; -   a 6-14-membered aryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 6-14-membered aryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted or substituted with one,     two, three or four substituents independently of one another     selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,     —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or     polysubstituted; wherein said 5-14-membered heteroaryl moiety is     optionally connected through —C₁-C₆-alkylene-, linear or branched,     saturated or unsaturated, unsubstituted or substituted with one,     two, three or four substituents independently of one another     selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,     —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; -   or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²²,     —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²²     together with the nitrogen atom to which they are attached form a     ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or     —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl,     linear or branched, saturated or unsaturated, unsubstituted or     substituted with one, two, three or four substituents independently     of one another selected from the group consisting of —F, —Cl, —Br     and —I; -   or a physiologically acceptable salt thereof.

Preferably, aryl includes but is not limited to phenyl and naphthyl. Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and -pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O— or —C(═O)O—CH₂—, said asymmetric group may be arranged in either direction. For example, when R⁴ is connected to the core structure through —C(═O)O—, the arrangement may be either R⁴—C(═O)O—core or core —C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁹ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In a preferred embodiment of the compound according to the invention, R¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹ means —H and R² means —CH₃.

In another preferred embodiment of the compound according to the invention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to the invention, R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃—.

In yet another preferred embodiment,

-   -   R¹ means —H or —CH₃; and     -   R² means a 3-12-membered cycloalkyl moiety, saturated or         unsaturated, unsubstituted; wherein said 3-12-membered         cycloalkyl moiety is connected through —CH₂—, unsubstituted;         preferably —CH₂-cycloalkyl, —CH₂-cyclobutyl or —CH₂-cyclopentyl;         or R² means a 3-12-membered heterocycloalkyl moiety, saturated         or unsaturated, unsubstituted; wherein said 3-12-membered         heterocycloalkyl moiety is connected through —CH₂—,         unsubstituted; preferably —CH₂-oxetanyl or         —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to the invention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted. In a preferred embodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted. More preferably, R³ means -phenyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F. In another preferred embodiment, R³ means —benzyl unsubstituted, mono- or polysubstituted. More preferably, R³ means -benzyl unsubstituted, mono- or disubstituted with —F, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F.

In still another preferred embodiment of the compound according to the invention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴ means —H.

In another preferred embodiment of the compound according to the invention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl, —OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O—)₁₋₃₀—CH₃, —C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl, —C(═O)NHC₁-C₄-alkylene—CN, —C(═O)NHC₁-C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂; —S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR²¹R²² wherein R²¹ and R²² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆, —(CH₂)₂—O—(CH₂)₂—, or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with —C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; or with —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH. More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or —C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to the invention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connected through —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to the invention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to the invention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵ means —H.

In another preferred embodiment of the compound according to the invention, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted, mono- or polysubstituted. More preferably, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C—S(═O)₂C —C(═O)—C₃₋₁₂heterocycloalkyl, —NH—C(═O)—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)₂ and NH—S(═O)₂—C₁-C₄-alkyl.

In still another preferred embodiment of the compound according to the invention, R⁵ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a 3-6-membered cycloalkyl moiety, saturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated, unsubstituted; more preferably -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —C₁-C₄-alkyl, wherein said -cyclopropyl, -cyclobutyl-cyclopentyl or -cyclohexyl is optionally connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a 4-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. More preferably, R⁵ means -hetero-cyclobutyl or -tetrahydro-2H-thiopyranyl dioxide, unsubstituted.

In yet another preferred embodiment of the compound according to the invention, R⁵ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a 5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted, wherein said 5-6-membered heteroaryl moiety is optionally connected through —CH₂—. More preferably, R⁵ means a 5-6-membered heteroaryl moiety, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl and —S—C₁-C₄-alkyl, wherein said 5-6-membered heteroaryl moiety is optionally connected through —CH₂—. Still more preferably, R⁵ means -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl and —S—C₁-C₄-alkyl, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl is optionally connected through —CH₂—.

In a further preferred embodiment of the compound according to the invention, R⁵ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl and —S—C₁-C₄-alkyl, wherein said -phenyl is optionally connected through —CH₂—.

In a preferred embodiment of the compound according to the invention, X means NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, X means NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 5-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. More preferably, X means NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which they are attached form -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH₂—OH and —C(═O)NH₂, wherein said —pyrrolidinyl, -piperidinyl, piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted.

In a preferred embodiment of the compound according to the invention R⁵ means —H;

-   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,     —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃,     —C(═O)N(CH₃)₂, —OH, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted     —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃; -   cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted     or monosubstituted with —F, —OH, —CN or —CH₃, wherein said     -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally     connected through —CH₂— or —CH₂CH₂—; -   -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each     case unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,     —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C₁-C₄-alkyl, —C(═O)OH, —C(═O)OCH₃,     —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH, —SCH₃, —S(═O)CH₃,     -S(═O)₂CH₃, unsubstituted -C(═O)-morpholinyl, -NH-C(═O)—CH₃,     —N(CH₃)₂ and NH—S(═O)₂—CH₃; wherein said -heterocyclobutyl,     -heterocyclopentyl, or -heterocyclohexyl is optionally connected     through —CH₂— or —CH₂CH₂—; -   -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,     -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or     5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,     —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃,     —S(═O)₂CH₃ and —S—CH₃, wherein said -oxazolyl, -isoxazolyl,     -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl,     -thiadiazolyl, -imidazolyl, -pyrimidinyl, or     5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally     connected through —CH₂—; or -   -phenyl, unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,     —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂     CH₃ and —S—CH₃, wherein said -phenyl is optionally connected through     —CH₂—; -   in case X means NR⁶, R⁶ means —H or —CH₃; -   or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to     which they are attached form a -pyrrolidinyl, -piperidinyl,     -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl     dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted     or substituted with one, two, three or four substituents     independently of one another selected from the group consisting of     ═O, —OH, —CH₂—OH, —C(═O)NH₂, and —S(═O)₂CH₃, wherein said     -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,     -thiomorpholinyl,- thiomorpholinyl dioxide or     -(methylsulfonyl)piperazinyl is optionally condensed with an     imidazole moiety, unsubstituted;

In a preferred embodiment of the compound according to the invention, X means NR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁶ means —H or —CH₃.

In preferred embodiments, the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):

wherein in each case

-   R¹, R², R³, R⁴, R⁵, R⁶ and X are defined as above, -   R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; -   R^(D) means —H or —F; -   or a physiologically acceptable salt thereof.

Preferably, the substructure of the compounds according to general formula (I) represented by R⁵, X, R⁹ and R¹⁰, i.e.

or the corresponding substructure of any of above general formulas (II-A) to (VIII-C) has preferably a meaning selected from the group consisting of:

In a particularly preferred embodiment of the compound according to the invention

-   R¹ means —H or —CH₃; -   R² means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂; -   R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted     or monosubstituted with —F; -   R⁴ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or     substituted with one, two, three or four substituents independently     of one another selected from the group consisting of —F, —Cl, —Br,     —I, —CN, —OH, ═O, —N(CH₃)₂ and —O—CH₃; or -   -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl,     unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein     said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is     connected through —CH₂— or —CH₂CH₂—; -   -oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or     —CH₃, wherein said -oxetanyl is connected through —CH₂— or —CH₂CH₂—; -   X means —O— or —NR⁶—; -   R⁵ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,     —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃,     —C(═O)N(CH₃)₂, —OH, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted     —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃; -   -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl,     unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein     said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is     optionally connected through —CH₂— or —CH₂CH₂—; -   -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each     case unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,     —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C₁-C₄-alkyl, —C(═O)OH, —C(═O)OCH₃,     —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH, —SCH₃, —S(═O)CH₃,     -S(═O)₂CH₃, unsubstituted -C(═O)-morpholinyl, -NH-C(═O)—CH₃,     —N(CH₃)₂ and NH—S(═O)₂—CH₃; wherein said -heterocyclobutyl,     -heterocyclopentyl, or -heterocyclohexyl is optionally connected     through —CH₂— or —CH₂CH₂—; -   -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,     -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or     5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,     —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃,     —S(═O)₂CH₃ and —S—CH₃, wherein said -oxazolyl, -isoxazolyl,     -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl,     -thiadiazolyl, -imidazolyl, -pyrimidinyl, or     5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally     connected through —CH₂—; or -   -phenyl, unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,     —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂     CH₃ and —S—CH₃, wherein said -phenyl is optionally connected through     —CH₂—; -   in case X means NR⁶, R⁶ means —H or —CH₃; -   or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to     which they are attached form a -pyrrolidinyl, -piperidinyl,     -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl     dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted     or substituted with one, two, three or four substituents     independently of one another selected from the group consisting of     ═O, —OH, —CH₂—OH, —C(═O)NH₂, and —S(═O)₂CH₃, wherein said     -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,     -thiomorpholinyl,- thiomorpholinyl dioxide or     -(methylsulfonyl)piperazinyed with an imidazole moiety,     unsubstituted; and -   R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean     —H.

In a particularly preferred embodiment of the compound according to the invention

-   R¹ means —H or —CH₃; and/or -   R² means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂; and/or -   R³ means -phenyl, -thienyl or -pyridinyl, in each case     unsubstituted; preferably, R³ means phenyl unsubstituted; and/or -   R⁴ means -   —H; —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or     substituted with one, two, three or four substituents independently     of one another selected from the group consisting of —F, —Cl, —Br,     —I, —CN, —OH, ═O, —N(CH₃)₂ and —O—CH₃; or -   -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl,     unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein     said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is     connected through —CH₂— or —CH₂CH₂—; preferably, R⁴ means     -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said     -cyclobutyl is connected through —CH₂—; and/or -   X means —O— or —NR⁶—; and/or -   R⁵ means -   —H; -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,     unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,     —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃,     —C(═O)N(CH₃)₂, —OH, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted     —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃;     preferably, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated or     unsaturated, unsubstituted or monosubstituted with —OH; -   -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl,     unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein     said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is     optionally connected through —CH₂— or —CH₂CH₂—; -   -heterocyclobutyl, -tetrahydro-2H-thiopyranyl dioxide,     —CH₂-heterocyclobutyl or —CH₂-tetrahydro-2H-thiopyranyl dioxide, in     each case unsubstituted; -   -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,     -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl,     in each case unsubstituted or substituted with one, two, three or     four substituents independently of one another selected from the     group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃,     —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂,     S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, wherein said -oxazolyl,     -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl,     -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl is optionally     connected through —CH₂-; preferably, R⁵ means -pyridinyl     unsubstituted; or -   -phenyl, unsubstituted or substituted with one, two, three or four     substituents independently of one another selected from the group     consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,     —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂     CH₃ and —S—CH₃, wherein said -phenyl is optionally connected through     —CH₂-; and/or -   in case X means NR⁶, R⁶ means —H or —CH₃; -   or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to     which they are attached form a -pyrrolidinyl, -piperidinyl,     -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl     dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted     or substituted with one, two, three or four substituents     independently of one another selected from the group consisting of     ═O, ═OH, —CH₂—H and —C(═O)NH₂, wherein said -pyrrolidinyl,     -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl,-     thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is     optionally condensed with an imidazole moiety, unsubstituted; and/or -   R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean     —H.

Preferably, the compound according to the invention is selected from the group consisting of

SC_1001 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1002 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester SC_1003 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1004 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1005 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1006 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester SC_1007 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide SC_1008 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide SC_1009 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide SC_1010 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide SC_1011 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide SC_1012 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide SC_1013 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1014 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1015 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide SC_1016 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1017 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1018 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide SC_1019 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide SC_1020 CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1021 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1022 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide SC_1023 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]- acetamide SC_1024 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide SC_1025 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethyl]-acetamide SC_1026 CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1027 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester SC_1028 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide SC_1029 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]-acetamide SC_1030 CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1031 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide SC_1032 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester SC_1033 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide SC_1034 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide SC_1035 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide SC_1036 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide SC_1037 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide SC_1038 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide SC_1039 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide SC_1040 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide SC_1041 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide SC_1042 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide SC_1043 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide SC_1044 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide SC_1045 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide SC_1046 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide SC_1047 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide SC_1048 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide SC_1049 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide SC_1050 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide SC_1051 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamidc SC_1052 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide SC_1053 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide SC_1054 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1055 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide SC_1056 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide SC_1057 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide SC_1058 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo- ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1059 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo- ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1060 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo- ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1061 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide SC_1062 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide SC_1063 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2- oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1064 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide SC_1065 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1066 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1067 CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide SC_1068 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1069 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide SC_1070 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1073 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide SC_1074 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide SC_1075 CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1076 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide SC_1077 CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1078 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1079 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid amide SC_1080 CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1081 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide SC_1082 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide SC_1083 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide SC_1084 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide SC_1085 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide SC_1086 CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1087 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide SC_1088 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide SC_1089 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide SC_1090 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide SC_1091 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide SC_1092 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide SC_1093 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide SC_1094 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide SC_1095 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide SC_1096 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide SC_1097 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide SC_1098 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide SC_1099 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide SC_1100 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide SC_1101 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide SC_1102 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide SC_1103 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide SC_1104 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide SC_1105 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid amide SC_1106 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide SC_1107 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide SC_1109 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide SC_1110 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide SC_1111 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide SC_1112 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1113 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2- oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1114 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1115 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1117 CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1118 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide SC_1119 ClS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide SC_1120 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide SC_1121 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1122 CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1123 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1124 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1125 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide SC_1126 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide SC_1127 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide SC_1128 CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1129 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide SC_1130 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide SC_1131 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1132 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1133 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide SC_1134 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1135 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1136 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1137 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1138 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide SC_1139 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1140 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide SC_1141 CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8- methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1142 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1143 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1144 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide SC_1145 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide SC_1146 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1147 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1148 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)- N-methyl-acetamide SC_1149 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1150 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide SC_1151 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide SC_1152 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1154 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo- ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1155 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1156 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1157 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1158 CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1159 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1160 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1161 CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1162 CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1163 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo- ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1164 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1165 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1166 CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1167 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1168 CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1169 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1171 CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3- yl)-acetyl]amino]-acetamide SC_1172 CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1173 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1174 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1175 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1176 CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1177 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1178 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1179 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide SC_1180 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1181 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide SC_1182 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)- ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1183 CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1184 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1185 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1186 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1187 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1188 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1189 CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1190 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1191 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1192 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1193 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide SC_1195 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1196 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1197 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-cthyl)-acetamide SC_1198 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-cthyl)-acetamide SC_1199 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1201 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amide SC_1204 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1205 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1206 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1207 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)- ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1208 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1209 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4- yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1210 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1211 CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1212 CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1213 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1214 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2- oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1215 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide SC_1216 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1- yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1217 CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1218 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide SC_1219 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide SC_1220 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide SC_1222 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1223 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide SC_1224 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide SC_1225 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide SC_1226 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide SC_1227 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide SC_1228 CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1229 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1230 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1231 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide SC_1232 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide SC_1233 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1234 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1235 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide SC_1236 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide SC_1300 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide SC_1301 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1302 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1303 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1304 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1305 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1306 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide SC_1308 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1- propyl-1,3-diazaspiro[4.5]decan-2-one SC_1309 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide SC_1310 CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1311 CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1312 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1313 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1- propyl-1,3-diazaspiro[4.5]decan-2-one SC_1317 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide SC_1318 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2- oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1319 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1320 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1321 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide SC_1322 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1323 CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1324 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1325 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1326 TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_1327 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1328 CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1329 TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1330 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2- hydroxy-ethyl)-N-methyl-acetamide SC_1331 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1- hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione SC_1332 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl- acetamide SC_1333 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1334 CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N- phenyl-acetamide SC_1335 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1336 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]- acetamide SC_1337 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)- methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione SC_1338 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2- (2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide SC_1339 CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)-acetamide SC_1340 CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide SC_1341 CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1342 CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)-acetamide SC_1343 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1344 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1345 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide SC_1346 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester SC_1347 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide SC_1348 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1349 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3- fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1350 CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide SC_1351 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl- piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1352 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1353 TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1354 TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1355 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4- methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1356 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1357 TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo- ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1358 TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1359 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide SC_1360 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4- fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1361 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin- 1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1362 CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide SC_1363 TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1364 TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1365 TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4- yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1366 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1- yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1368 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1- hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1369 TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- acetamide SC_1370 TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1371 CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2- (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_1372 CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3- trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one and the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise, “—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can be linear or branched, saturated or unsaturated. Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.

According to the invention, unless expressly stated otherwise, “—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can be unsubstituted, mono- or polysubstituted. Examples of substituted alkyl include but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂, and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise, “—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of saturated alkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—, —CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkylene include but are not limited to —CH═CH—, —C≡C—, —C(CH₃)═CH—, —CH═C(CH₃)—, —C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise, “—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of substituted —C₁-C₆-alkylene- include but are not limited to —CHF—, —CF₂—, —CHOH— and —C(═O)—.

According to the invention, moieties may be connected through —C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring. Examples of preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline. Examples of preferred unsaturated 3-12-membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered cycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene- linker. Examples include but are not limited to —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and —CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, morpholine, thiomorpholine. Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties. Examples of 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety. An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety. An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety. Examples include but are not limited to —CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine, —CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and —CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring. Examples of preferred 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren. The 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety. An example of a 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH₂—C₆H₅, —CH₂CH₂-C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The 5-14-membered heteroaryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety. An examples of a 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety. Examples of 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety. Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole, —CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine, —CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine, —CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted. Examples of 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.

Preferably, the compounds according to the invention have a structure according to general formula (I′)

wherein R¹ to R⁵, R⁹ to R²⁰, and X are defined as above, or a physiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.

Preferably, the compounds according to the invention have a structure according to general formula (IX)

wherein

-   R^(C) means —H or —OH; -   R³ means -phenyl or -3-fluorophenyl; -   R⁵ means —H, —CH₃, —CH₂CH₂OH, or —CH₂C(═O)NH₂; -   R⁶ means —H or —CH₃; -   or R⁵ and R⁶ together with the nitrogen atom to which they are     attached form a ring and mean —(CH₂)₅—, wherein said ring is     unsubstituted or substituted with one or two substituents     independently of one another selected from the group consisting of     —CH₃, —OH, —S(═O)₂CH₃ and —C(═O)NH₂; -   R⁹ and R¹⁰ independently of one another mean —H or —CH₃; -   or a physiologically acceptable salt thereof.

In a preferred embodiment, the compounds according to the invention are in the form of the free bases.

In another preferred embodiment, the compounds according to the invention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. The term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions. Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.

Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals. Examples of physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according to the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are ²H (deuterium), ³H (tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both. The pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors. Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors. Compounds according to the invention having agonist activity may be either full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”. Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.

In certain embodiments, the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor as well as agonist activity at the         KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor as well as agonist activity at the         DOP receptor;     -   can be regarded as opioid pan agonists, i.e. have agonist         activity at the NOP receptor as well as agonist activity at the         MOP receptor as well as agonist activity at the KOP receptor as         well as agonist activity at the DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         DOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         KOP receptor as well as no significant activity at the DOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor as well as agonist activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor as well as agonist activity at the         DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         DOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the DOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         KOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the KOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the NOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the NOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the NOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor;     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor as well as agonist activity at the NOP         receptor;     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor as well as antagonist activity at the NOP         receptor; or     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor;     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor;     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         KOP receptor; or     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the KOP         receptor.

For the purpose of the specification, “no significant activity” means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according to the invention as medicaments.

A further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain. A further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human. The pain is preferably acute or chronic. The pain is preferably nociceptive or neuropathic.

A further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence. A further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human

Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.

Preferably, the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.

The pharmaceutical composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.

Examples of suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.

Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.

In one preferred embodiment, the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous administration preparations.

The amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.

Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.

In yet another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of

-   -   an intermediate according to general formula (IIIa) and         according to general formula (IIIb); or     -   an intermediate according to general formula (IIIa) and         according to general formula (IIIc); or     -   an intermediate according to general formula (IIIb) and         according to general formula (IIIc); or     -   an intermediate according to general formula (IIIa), according         to general formula (IIIb) and according to general formula         (IIIc).

The following examples further illustrate the invention but are not to be construed as limiting its scope.

EXAMPLES

RT means room temperature (23±7° C.), M are indications of concentration in mol/l, aq. means aqueous, anhydr. means anhydrous, sat. means saturated, sol. means solution, “conc.” means concentrated.

Further Abbreviations:

-   brine saturated aqueous sodium chloride solution -   CC column chromatography -   cHex cyclohexane -   DCM dichloromethane -   DIPEA N,N-diisopropylethylamine -   DMF N,N-dimethylformamide -   EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -   Et ethyl -   ether diethyl ether -   EE ethyl acetate -   EtOAc ethyl acetate -   EtOH ethanol -   h hour(s) -   H₂O water -   HATU     O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate -   LDA Lithium-di-isoproyl-amid -   Me methyl -   m/z mass-to-charge ratio -   MeOH methanol -   MeCN acetonitrile -   min minutes -   MS mass spectrometry -   NBS N-bromo-succinimide -   NEt₃ triethylamine -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) -   PE petroleum ether (60-80° C.) -   RM reaction mixture -   RT room temperature -   T3P     2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide -   tBME tert-butyl methyl ether -   THF tetrahydrofuran -   TFA trifluoroacetic acid -   v/v volume to volume -   w/w weight to weight -   XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. All temperatures are uncorrected.

All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington D.C., US, repspectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography are specified in v/v.

All the intermediate products and exemplary compounds were analytically characterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition ¹H-NMR and ¹³C spectroscopy was carried out for all the exemplary compounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

Synthesis of Intermediates

Synthesis of INT-799: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspirop.51decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×300 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with DCM (3×150 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS dimethylamino-1-[(1-hydroxy -cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]⁺358.2

Synthesis of INT-951: CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1: 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10 min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was allowed to stir at RT for 3 h, then quenched with water and the organic product was extracted with ethyl acetate (3×200mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.

Step 2: 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide

TFA (100mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with dichloromethane (3×150mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 3.5 g (crude) of 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide. The material was used for the next step without further purification.

Step 3: 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile

Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography to afford 1.3 g (34% after three steps) of CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile (INT-951). [M+H]⁺367.2.

Synthesis of INT-952: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to reflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, and stirring was continued at reflux for 12 h. KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added again. The reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na₂SO₄ and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. The filtrate was concentrated in vacuo and the resulting solid was recrystallized from hot ethanol to yield 7.8 g of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952). [M+H]⁺461.3.

Synthesis of INT-953: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwise and stirring was continued for 50 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified column chromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4); R_(f)=0.48.

Step 2: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. The reaction mixture was warmed up to RT and stirred for 16 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted with EtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether (1:3)→(3:7)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4); R_(f)=0.40.

Step 3: 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol) and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and the reaction mixture was stirred for 10 min at 0° C. (ice bath). A solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were added and the reaction mixture was stirred at 45° C. for 20 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml), the combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1); R_(f)=0.45. The product was used for the next step without additional purification.

Step 4: CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was cooled in an ice bath (−0° C.) and a solution of phenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5° C. The ice bath was removed and the reaction mixture was stirred for 30 min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc (4×30 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified by column chromatography (silica gel, 230-400 mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to give CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); R_(f)=0.6

Step 5: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was cooled in an ice bath and a mixture of TFA/CH₂Cl₂ (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixture was warmed to RT and stirred for 20 h, then quenched with methanolic NH₃ (10 ml, ˜10% in MeOH) and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified twice by column chromatography (silica gel, 230-400 mesh, eluent: MeOH—CHCl₃ (1:99)→(2:98)) to give CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95); R_(f)=0.25; [M+H]⁺384.3

Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH₄Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether ; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C.

The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO₃ and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45). [M+H]⁺201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h using Dean Stark apparatus. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO₃ and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 45.0 g (85%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a light brown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂O₂ (210.0 mL, 1844.2 mmol) were added to the solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g, 184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture was stirred at RT for 14 h. The reaction mixture was diluted with water (1.5 L) and stirred for 1 h. The precipitated solid was separated by filtration, washed with water, petroleum ether and dried under reduced pressure to get 32.0 g (66%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white solid. (TLC system: 10% MeOH in DCM R_(f): 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5wt % aq. solution, 700 mL, 477.09 mmol) and KF—Al₂O₃ (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×500 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 18.0 g (66%) of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brown solid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64 mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. The reaction mixture was filtered through celite pad, the solid residue was washed with water and the combined filtrate was extracted with EtOAc (4×200 mL). The combined organic layer washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown semi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35wt % aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH₄Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 10.5 g (72%) of 4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a light brown solid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro[4.5]-decan-8-one (35g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 44 g of 8-(dimethylamino)-1,4-dioxaspiro[4.5]-decane-8-carbonitrile (93%) as a white solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3M phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. under argon atmosphere. The reaction mixture was stirred for 4 h at −10° C. to 0° C. and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., diluted with sat. aq. NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 60 g of, N N-dimethyl-8-phenyl-1, 4-dioxaspiro[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×150 mL).

The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H]⁺218.1

Synthesis of INT-966: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) were added to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction mixture was stirred at 60° C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., the precipitated solid was filtered off and dried in vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{{circumflex over ( )}5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2×1.5 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford additional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (TLC system: 10% Methanol in DCM; Rf: 0.4).

Step 2: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Cl (1.0L) and the organic product was extracted with EtOAc (2×1.5L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione as an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argon atmosphere and the resulting mixture was stirred at RT for 1 h. 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (150 g, 433. 05 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO₃ (500 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 120 g (84%) of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}2{circumflex over ( )}{5}]tetradecan-3-one as an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}×{5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×2.0L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0L). Combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 90 g of 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4) [M+H]⁺289.11.

Synthesis of INT-971: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2mL) was added to the solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification of the residue by preparative TLC (3% MeOH in DCM as mobile phase) yielded 50 mg (18%) of CIS (Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20) [M+H]⁺478.3

Synthesis of INT-974: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).

Step 2: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) was added dropwise to a solution of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NH₄Cl (200 mL) and the organic product was extracted with EtOAc (2×200mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g×2 and 5 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol in DCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%) of CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1). [M+H]⁺412.2

Synthesis of INT-975: CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH₄Cl (150mL) and the organic product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The reaction was carried out in 2 batches (8 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) as a white solid. [M+H]⁺394.2

Synthesis of INT-976: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT under argon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf: 0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g, 34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 4 h at 60° C. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated Na₂SO₄ solution (100 mL) and filtered through Celite pad. The filtrate was dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 5.7 g (59%) of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS- and TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g, 29.30 mmol) was purified by preparative chiral SFC (column: Chiralcel AS—H, 60% CO₂, 40% (0.5% DEA in MeOH)) to get 5 g of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) as a white solid. [M+H]⁺274.2.

Synthesis of INT-977: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt

Step 1: CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester

A solution of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was was allowed to warm up to RT over 30 min. The solution was then cooled to 0° C. again and tert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RT for 16 h, quenched with water and extracted with DCM (3×). The combinded organic layers were dried over Na₂SO₄, filtered and concentrated inder reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4 g).

Step 2: cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid trifluoroacetic acid salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H]⁺332.2

Synthesis of INT-978: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid00 (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extracted with DCM (3×5mL), the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H]⁺359.2

Synthesis of INT-982: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RT for 10 min. CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for 15 min 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added at 0° C. The reaction mixture was heated to 60° C. for 16 h. After cooling down to RT, water (100 mL) was added and the mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with water (70 mL), brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Purification of the residueby column chromatography on silica gel provided CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light yellow solid.

Step 2: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution of CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. The organic layer was separated and washed with brine (40 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. Crystallization of the residue from EtOAc provided CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H]⁺356.3

Synthesis of INT-984: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step2: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).

Synthesis of INT-986: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH ˜10 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with 5N aq. NaOH to pH ˜10 and extracted with DCM (3×10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give 3.5 g (crude) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyhmethyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to the solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The reaction mixture was stirred at RT for 3 h, then quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g (62%) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether; R_(f): 0.65).

Step 3: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (˜25 mL) at −78° C. The resulting mixture was stirred for 10min at −78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH₄Cl, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3×50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f): 0.15.). [M+H]^(+356.3)

Synthesis of INT-987: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).

Synthesis of INT-988: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL), stirred for 10 minutes, 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture was stirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue (283 mg yellow oil) was purified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to 96/4) to give 8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).

Step 2: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)

In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H)⁺.

Synthesis of INT-992: CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid

CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-241) (0.9 g, 273 mmol) was added to a solution of NaH (60wt % in mineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at R.T. for 15 min, then cooled to 0° C. and ethyl 2-bromoacetate (4.56 g, 27.35 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 days. The reaction completion was monitored by TLC. The reaction mixture was quenched with water and concentrated under reduced pressue. The residue was diluted with small amount of water and acidified by acetic acid. The resulting mixture was concentrated under reduced pressure again. The crude product was purified by silica gel flash chromatography using 230-400 mesh (25 vol % MeOH in DCM) to afford 1.1 g of CIS-2-[8-dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-992) as a solid. [M+H]⁺388.3

Synthesis of INT-994: CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid

Step 1: ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3 yl)acetate

KOtBu (1M in THF) (54.90 mL, 54.95 mmol) was added to a solution of CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 15 min. A solution of ethyl bromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL) was added. The reaction mixture was warmed up to RT and stirred for 48 h. The reaction completion was monitored by TLC. Solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield the desired product in 2 fractions: fraction 1: 2.2 g ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure according to LCMS) as an off-white solid and Fraction 2: 3.2 g of ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (32% pure according to LCMS) as well as 1.1 g of unreacted starting material. Fraction 1 was used further without additional purification.

Step 2: 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid

A mixture of ethyl-2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure, 2.2 g, 6.128 mmol) and powdered NaOH (981 mg, 24.513 mmol) in toluene (40 mL) was stirred at 80° C. for 3 h under argon atmosphere. Ester hydrolysis was monitored by LCMS. Toluene was evaporated under reduced pressure and the resulting crude product (2.4 g) was further purified by reverse phase prep. HPLC to yield 0.93 g of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid.

Step 3: 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid

To a solution of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (1.5 g, 4.532 mmol) in toluene (45 mL) was added in one portion powdered NaOH (725.08 mg, 18.127 mmol) under argon atmosphere at RT. The reaction mixture was stirred at 80° C. for 4 h. Toluene was evaporated under reduced pressure to get the residue which was dissolved in DMSO (45 mL) under argon atmosphere. The solution was stirred at 55° C. for 1 h. To the reaction mixture was added dropwise a solution of 1-oxaspiro[2.3]hexane (1.144 g, 13.596 mmol) in DMSO (12 mL) via syring pump (flow rate 10 mL/h). The reaction mixture was stirred at 55° C. for 65 h. The reaction progress was monitored by LCMS. DMSO was evaporated in vacuo. The residue was dissolved in water (50 mL), cooled to 0° C. and pH was adjusted to 3-4 with acetic acid. The resulting mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (elution with 8-10% MeOH in DCM) to yield 750 mg (78%) of 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (INT-994) as an off-white solid. [M+H]⁺416.2

Synthesis of INT-998: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt

Step 1: CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate

CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (2.8 g, 7.9 mmol) was dissolved in THF (110 mL) and the solution was cooled to 0° C. Lithium diisopropylamide solution in THF/heptane/ethylbenzene (2M, 16 mL) was added dropwise. The reaction mixture was stirred for 30 min and t-butyl-bromoacetate was added dropwise at the same temperature. The reaction mixture was concentrated in vacuo, water was added and the resulting mixture was extracted with DCM (3×250 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate (1670 mg) as a white solid.

Step 2: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt

CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]decan-3-yl]acetat (2250 mg, 4.8 mmol) was teated with TFA (18 mL) at RT. After stirring for 10 min, all volatiles were removed in vacuo. The residue was triturated with diethyl ether (30 mL) using ultrasonic bath, the solid rest was dried under reduced pressure to yield CIS-2-[8-dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-998) (2.2 g) as a brown solid. [M+H]⁺413.3

Synthesis of INT-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) in EtOH (30 mL) was stirred at RT for 48 h. The reaction mixture was concentrated under argon atmosphere. The residue was diluted with ether (60 mL) and added to the freshly prepared PhLi solution [prepared by addition of 2.5M n-BuLi in THF (70.5 mL, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100 mL) at −30° C. and stirred at RT for 1 h] at RT. The reaction mixture was stirred at RT for 1.5 h, then cooled down to 0° C. and quenched with sat. aq. NH₄Cl (100 mL). The resulting mixture was extracted with EtOAc (2×750 mL), combined organic extracts were washed with water (3×350 mL), brine (300 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was dissolved in ethylmethyl ketone (100 mL) and TMSCl (37.5 mL) was added at 0° C. The reaction mixture was stirred at RT for 16 h, the precipitate formed was filtered off and washed with acetone and THF to give ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as an off-white solid. This reaction was done in 2 batches of 25 g scale and the yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was added conc. HCl (62.5 mL) at 0° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was basified with 1N aq. NaOH to pH ˜14 at 0° C. and extracted with DCM (2×750 mL). Organic layer was washed with water (400 mL), brine (400 mL), dried over Na₂SO₄ and concentrated under reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the next step without further purification. This reaction was carried out in another batch of 15.1 g scale and yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: mixture of CIS- and TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol, 1.0 eq.) in EtOH (250 mL) and water (200 mL) was added (NH₄)₂CO₃ (18.8 g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min KCN (5.09 g, 78.341 mmol, 1.0 eq.) was and the resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to RT, the precipitate was filtered off, washed with water (250 mL), EtOH (300 mL), hexane (200 mL) and dried under reduced pressure to yield CIS- and TRANS-mixture 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol). LC-MS: m/z [M+1]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)

To a solution of cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) in MeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric acid in MeOH (25 mL). The resulting mixture was stirred at RT for 2 h and then kept in refrigerator for 16 h. The solid material was filtered off and washed with MeOH/DCM (1:5, 50 ml) to get 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5 g) as a white solid. The solid was suspended in sat. aq. NaHCO₃ (pH ˜8) and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combined organic extracts were washed with water (300 ml), brine (300 ml) and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and the residue was triturated with 20% DCM-hexane to afford CIS ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as a white solid. This step was done in 2 batches (12 g & 2.4 g) and yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol). LC-MS: m/z [M+1]⁺=288.0.

Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.905 mmol, 3.0 eq.) in THF (15 mL) was added a suspension of cis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g, 6.968 mmol, 1.0 eq.) in THF (60 mL) at 0° C. and the reaction mixture was stirred at 65° C. for 16 h. The resulting mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1 h and filtered through celite. The celite layer was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting crude product was triturated with 15% DCM—Hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol). LC-MS: m/z [M+H]⁺=274.2.

Synthesis of INT-1019: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride

Step 1: tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

The solution of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (1.8 g, 5.042 mmol) in THF (40 mL) was cooled down to 0° C. and KOtBu (1 M in THF, 5.55 mL, 5.546 mmol) was added. The resulting mixture was stirred for 10 min followed by the dropwise addition of tert-butyl bromoacetate (1.081 g, 5.546 mmol). The ice bath was removed and the reaction mixture was stirred for 2 h, then quenched with sat. aq. NH₄Cl (40 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. Crude product was purified by column chromatography (silica gel 100-200 mesh, 0-4% MeOH in DCM as eluent) to afford 1.7 g of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate as an off white solid.

Step 2: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride

4N HCl in dioxane (30 mL) was added to the solution of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (1.7 g, 3.609 mmol) in 1,4 dioxane (10 mL). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure to afford 1.5 g of CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride (INT-1019) as a hygroscopic solid. TLC R_(f) (10% MeOH in DCM)=0.2. LC-MS: m/z [M+H]⁺=416.3.

Synthesis of INT-1020: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

Step 1: tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

To the suspension of tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1018) (0.5 g, 1.74 mmol) in DMF (11 mL) was added portionwise sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol, 1 equiv.). The reaction mixture was stirred until the evolution of hydrogen was over and a clear solution was formed (ca. 40 min). Tert-butyl bromoacetate (257 μL, 1.74 mmol, 1 equiv.) was added, the reaction mixture was stirred at RT overnight, quenched with ca. 40 mL water and stirred for 2 h. The precipitate was filtered off, washed with water, hexane and dried under reduced pressure to give tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (653 mg, 93%) which was used further without additional purification. LC-MS: m/z [M+H]⁺=402.2.

Step 2: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020)

Sodium hydroxide (135 mg, 3.37 mmol, 4 equiv.) was suspended in dimethyl sulfoxide (1.8 mL, 25.26 mmol, 30 equiv.) and the mixture was stirred at RT for 10 min Tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (338 mg, 0.84 mmol, 1 equiv.) was added, the reaction mixture was stirred 5 min at RT and then heated up to 50° C. [1-[Tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl 4-methylbenzenesulfonate (936 mg, 2.53 mmol, 3 equiv.) was added and the reaction mixture was stirred at 60° C. for 3 days. The resulting mixture was cooled down to RT, diluted with water (5 mL), extracted with EtOAc (1×10 mL) and the aqueous phase was concentrated under reduced pressure to give crude sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020) (473 mg) which was used in the next step without further purification. LC-MS: m/z [M+H]⁺=452.2.

Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO₃ (500 mL) over a period of 30 min The organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g (crude) of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2: 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at −10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added to a solution of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)prop ane-2-sulfinamide (6.0g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4: 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and solvent was concentrated under reduced pressure to get 3 g (crude) of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5: N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and to the residue sat. aq. NaHCO₃ was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) of N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6: 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added to N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RT for 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 2.0 g (crude) of 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7: 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone (1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RT under argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with ice-water and the organic product was extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g (crude) of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H₂O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B%): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.

Step 9: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)

LiAlH₄ (1 M in THF) (4.48 mL, 4.48 mmol) was added to a solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄ (1000 mL) and filtered through celite pad. The filtrate was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952 CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) was converted into CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).

Synthesis of INT-1032: CIS-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate

In analogy to the method described for INT-998 step 2 2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) was converted into 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate (INT-10322).

Synthesis of INT-1034: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid

Step 1: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

In analogy to the method described for INT-988 Step 1 CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-967) was converted into CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (INT-1033). LC-MS: m/z [M+H]⁺=388.3

Step 2: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

To a suspension of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) (8.1 g, 20.90 mmol, 1.0 eq.) in DMF (300 mL) was added NaH (603 mg, 25.11 mmol, 1.2 eq.) at RT and the reaction mixture was stirred for 40 min Trimethylsilylethoxymethyl chloride (SEMCl) was added (4.06 ml, 23.02 mmol, 1.1 eq). The resulting mixture was stirred at RT for 16 h, then diluted with ice-water (100 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water (150 mL), brine (200 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexane) to yield CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (4.0 g, 7.736 mmol, 37%) as a light yellow dense sticky liquid. LC-MS: m/z [M+H]⁺=518.3

Step 3: CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester

In analogy to the method described for INT-986 Step 1 CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester was converted into CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester. LC-MS: m/z [M+H]⁺=504.2

Step 4: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034)

To a solution of CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (1.6 g, 3.180 mmol, 1.0 eq.) in MeOH (48 mL) was added 2N aq. HCl (48 mL) and the mixture was stirred at RT for 16 h. The reaction mixture concentrated under reduced pressure, diluted with MeOH (40 mL), basified with 1M aq. LiOH (pH ˜12) and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH ˜6 with aq. NaHSO₄. The reaction mixture was extracted with 20% MeOH/DCM (5×200 ml). The combined organic layer was dried over anhydr. Na₂SO₄ and concentrated under reduced pressure to yield CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034) (850 mg, 0.681 mmol, 84%) as an off white solid. The product was used in the next step without further purification. LC-MS: m/z [M+H]⁺=318.2

Synthesis of INT-1035: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid

Step 1: CIS -(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester

In analogy to the method described for INT-986 Step 1 CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) was converted into CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester.

Step 2: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035) Synthesis of INT-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C. 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C. The reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C. The reaction mixture was cooled down to 0° C., quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added and the resulting mixture was stirred for 2 h and then left without stirring for 2 h at RT. The precipitate was filtered off and washed with EtOAc and MeOH. The resulting solid residue was suspended in methanol and stirred at RT overnight. The precipitate was filtered off and disposed. The filtrate was concentrated under reduced pressure, the residue was suspended thoroughly in water (50 mL) at 40° C., the precipitate was filtered off and dried under reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one was treated with conc. aq. HCl to be converted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)

In analogy to the method described for INT-965 step 1 1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine and potassium cyanide to be converted into 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038: CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1M bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the reaction mixture was stirred for 1 h at RT. Additional portion of 1M bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The reaction mixture was stirred at RT overnight, then quenched with methanol/water. Solid NH₄Cl and DCM were added to the resulting mixture and the precipitate was filtered off. The organic phase of the filtrate was separated and the aqueous phase was extracted with DCM (3×). The combined organic phases were dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 100/0 to 65/35) to yield CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1059: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added (NH₄)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. The reaction mixture was stirred at 60° C. for 18 h and then filtered in hot condition to get white solid which was washed with water (2.5 L), ethanol (1 L) and hexane (2.5 L). The resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid. The filtrate was collected from multiple batches (˜450 g) which contained a mixture of cis and trans isomers. The filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get ˜100 g of a mixture of cis and trans (major) isomers. Crude material was partially dissolved in hot MeOH (600 mL) and cooled to RT, filtered through sintered funnel, washed with MeOH (200 mL) followed by ether (150 mL) and dried to get TRANS -8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50 g, 0.174 mmol, ˜9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)

In analogy to the method described for INT-976 step 2 TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH₄ to be converted into TRANS -8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS- and TRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH (400 mL) was added NH₄Cl (24.6 g, 460.8 mmol) followed by NH₄OH (400 mL) at RT and the reaction mixture was stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with DCM (3×750 mL). Combined organic layer was washed with water (750 mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as an off white solid which was used in next step without further purification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2: N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at RT for 16 h, then diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×250 mL). Combined organic layer was washed with brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to get crude N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide as a light yellow sticky material which was used in the next step without further purification. LC-MS: m/z [M+1]⁺=339.9 (MW calc. 339.36).

Step 3: 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40 mL) was added N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide (6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. Na₂SO₄ at 0° C., excess THF was added and the resulting mixture was stirred at RT for 2 h. The resulting suspension was filtered through celite and the filter cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate was concentrated under reduced pressure to yield crude 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, crude) as a light yellow sticky material which was directly used in the next step without further purification. LC-MS: m/z [M+1]⁺=330.0 (MW calc. 329.40).

Step 4: CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)

To a solution of 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition of COCl₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. and stirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃ solution and extracted with DCM (2×200 ml). Combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to get crude product which was purified by prep HPLC to get CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC) and TRANS-8-dimethyl amino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]⁺=356.2 (MW calc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5 μ, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R_(t)=5.17 min. ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.43-7.27 (m, 5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

To a solution of CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester (300 mg, 0.636 mmol, 1.0 eq.) in THF/H₂O (8 mL, 1.5:1) was added LiOH (160 mg, 3.821 mmol, 6.0 eq.). The reaction mixture was stirred at RT for 16h, concentrated under reduced pressure, neutralized with aq. NaHSO₄ to pH ˜6 and extracted with 5% MeOH/DCM (3×200 mL). the combined organic extract was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with 15% DCM-Hexane to yield CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035) (210 mg, 0.523 mmol, 82%) as an off-white solid.

For further intermediates the synthesis in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.

in analogy m/z Intermediate Chemical Name Chemical structure to method [M + H]⁺ INT-241 CIS-8- (dimethylamino)-1- isobutyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-982 330.3 INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-975 424.3 INT-796 CIS-8-Dimethylamino- 3-[(4-methoxyphenyl)- methyl]-8-(3-methoxy- propyl)-1,3- diazaspiro[4.5]decan-2- one

INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl-1- methyl)-8- dimethylamino-8- phenyl-3-[phenyl- methyl-1,3- diazaspiro[4.5]decan-2- one

INT-952 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)- cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl- cyclohexan-1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H- pyrazol-3-yl)-4-oxo- cyclohexane-1- carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1- carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3- yl)-cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl- cyclohexan-1-one

INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)- cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-975 364.2 INT-964 4-(Ethyl-methyl- amino)-4-phenyl- cyclohexan-1-one

INT-965 232.2 INT-967 CIS-8-Dimethylamino- 8-[4-(methoxymethyl- oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5] decan-2-one

INT-974 454.3 INT-968 CIS-8-Dimethylamino- 8-[3-(methoxymethyl- oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5] decan-2-one

INT-974 454.3 INT-969 CIS-1-(Cyclobutyl- methyl)-8- dimethylamino-8-(4- hydroxyphenyl)-3-[(4- methoxyphenyl)- methyl]-1,3-diazaspiro [4.5]decan-2-one

INT-971 478.3 INT-970 CIS-8-Dimethylamino- 8-(4-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-972 CIS-8-Dimethylamino- 8-(3-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-973 CIS-8-Dimethylamino- 8-(4-fluorophenyl)-3- [(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

INT-974 412.2 INT-979 CIS-8-Dimethylamino- 1-(3-methoxy-propyl)- 8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 346.2 INT-980 CIS-8-Dimethylamino- 1-(2-methoxy-ethyl)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 332.2 INT-981 CIS-8-Dimethylamino- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 328.2 INT-985 CIS-1-(Cyclobutyl- methyl)-8-(methyl- propyl-amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-986 370.3 INT-989 CIS-2-[1-[(1-Cyano- cyclobutyl)-methyl]-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid

INT-992 425.2 INT-990 CIS-2-[8- Dimethylamino-1-(3- methoxy-propyl)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid

INT-992 404.2 INT-991 CIS-2-[1-(Cyclopropyl-1- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid

INT-992 386.2 INT-993 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid

INT-992 400.3 INT-995 CIS-2-(8- Dimethylamino-2-oxo- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3- yl)-acetic acid

INT-992 374.2 INT-996 CIS-2-[8- Dimethylamino-1- [(dimethyl-carbamoyl)- methyl]-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt

INT-998 417.2 INT-997 CIS-2-[8- Dimethylamino-1-(2- methoxy-ethyl)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- y]-acetic acid; 2,2,2- trifluoro-acetic acid

INT-998 390.2 INT-999 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt

INT-998 400.3 INT-1000 4-benzyl-4- (dimethylamino)cyclo- hexanone

INT-965 232.3 INT-1001 CIS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-1002 TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-1009 CIS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one

INT-976 280.1 INT-1010 TRANS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one

INT-976 280.1 INT-1011 4-(dimethylamino)-4- (1-methyl-1H- benzo[d]imidazol-2- yl)cyclohexanone

INT-965 272.2 INT-1012 CIS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one

INT-976 328.2 INT-1013 TRANS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one

INT-976 328.2 INT-1014 CIS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetic salt

steps 1 and 2 of INT- 994 332.2 INT-1015 CIS-2-(8-(ethylamino)- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1016 TRANS-8- (ethylamino)-8-phenyl- 1,3- diazaspiro[4.5]decan-2- one

INT-1008 274.2 INT-1017 TRANS-2-(8- (ethylamino)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1018 CIS-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decane- 2,4-dione

INT-976 288.2 INT-1024 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-977 (step 2) 292.2 INT-1025 CIS-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-974, INT-977 (step 2) 292.2 INT-1039 CIS-8- (dimethylamino)-8-(3- (trifluoromethoxy) phenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 358.2 INT-1040 (CIS)-8- (dimethylamino)-8-(3- (trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one

INT-1038 342.2 INT-1041 (CIS)-8- (dimethylamino)-8-(3- methoxyphenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 304.2 INT-1042 (CIS)-8-(5- chlorothiophen-2-yl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 314.1 INT-1043 (CIS)-8- (dimethylamino)-8-(3- fluoro-5- methylphenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 306.2 INT-1044 (CIS)-8-(3- chlorophenyl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 308.2 INT-1047 (CIS)-8- (methyl(oxetan-3- ylmethyl)amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-1026 330.5 INT-1057 CIS-1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1031 360.3 INT-1058 CIS-2-(1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-2-oxo- 1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate

INT-998 418.3 INT-1060 TRANS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1061 TRANS-1- (cyclopropyl-methyl)- 8-dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 328.2 INT-1062 TRANS-2-[1- (cyclopropyl-methyl)- 8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid trifluoroacetic salt

INT-998 386.2 INT-1063 CIS-1- (cyclopropylmethyl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-987 342.3 INT-1067 TRANS-2-[1- (cyclobutyl-methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt

INT-998 400.3 INT-1070 CIS-8- (dimethylamino)-8- phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1068 360.2 INT-1074 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1-((1- hydroxycyclobutyl) methyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1031 376.2

Synthesis of Exemplary Compounds

Synthesis of SC_1051: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide

Into a dry reaction vessel were added successively 1 mL of a solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-993) (0.1 M in DCM), 2 mL of a solution of 5-methoxy-pyridin-2-amine (0.2 M in DCM), 0.07 ml of triethylamine and 0.118 mL of a solution of T3P (1.7 M, 50% in EtOAc). The reaction mixture was stirred at RT overnight, then quenched with 3 mL aq. Na₂CO₃ (1 M) and stirred at RT for 1 h. The organic layer was separated and the aq. layer was extracted with DCM (2×). The combined organic layers were concentrated under reduced pressure and the resulting crude product was purified by HPLC to obtain CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide (SC_1051). [M+H]⁺506.3

Synthesis of SC_1073: CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide

To a mixture of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid trifluoroacetate (INT-999) (100 mg, 0.19 mmol) and 2-amino-N-methylisonicotinamide (118 mg, 0.78 mmol) in DCM (6 ml) were added HATU (148 mg, 0.39 mmol) and DIPEA (0.13 ml, 0.78 mmol) at RT and the reaction mixture was stirred at same temperature for 16 h. The reaction mixture was washed with 1M aq. Na₂CO₃ (1 mL) and 2M aq. NaOH (1 mL). The combined aqueous layers were extracted with DCM (3×5mL). The combined organic layers were washed with water (3 mL) and brine (3 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography (silica gel, cHex/tBuOMe/1N methanolic ammonia 1:1:0.05) of the crude product provided CIS-2-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide (SC_1073) (27 mg). [M+H]⁺533.3

Synthesis of SC_1076: CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide

CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1026) (30 mg, 0.06 mmol) was dissolved in DMSO (0.2 mL) and potassium carbonate (17 mg, 0.12 mmol) and hydrogen peroxide (30% in water, 0.12 mmol) were added at 0° C. The resulting mixture was stirred for 18 h, then water was added and the reaction mixture was extracted with DCM (3×5mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and the resulting crude product was purified by flash chromatography to yield CIS-6-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide SC_1076 (14 mg) as a white solid. [M+H]⁺519.3

Synthesis of SC_1110: CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide

A solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide (SC_1070) (80 mg, 0.16 mmol) in DCM (12 mL) was cooled to 0° C. and treated with a boron tribromide solution (1M in DCM, 1.26 mL, 1.26 mmol). After stirring at RT for 16 h the reaction mixture was quenched with MeOH, diluted with water and extracted with DCM (3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuum. The resulting crude product was purified by column chromatography (reversed phase silica gel C18, water/MeCN 100:0->20:80) to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide (SC_1110) (17 mg). [M+H]⁺493.3

Synthesis of SC_1128: CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide

CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1195) (50 mg, 0.1255 mmol), 4-bromopyrimidine-2-carbonitrile (0.1882 mmol), 4,5-XantPhos (0.0188 mmol), Cs₂CO₃ (0.2509 mmol) and Pd₂(dba)₃ (0.0063 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was degassed by three consecutive vacuum/nitrogen-refill cycles and then stirred at 90° C. for 18 h. Water (2 mL) was added and the resulting mixture was extracted with ethyl acetate (3x6 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography to yield CIS-N-(2-cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1128) (43 mg) as a white solid. [M+H]⁺502.3

Synthesis of SC_1129: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide

CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide SC_1120 (30.0 mg) was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mL) and hydrogen peroxide (30% in water, 12 μL) was added. The resulting mixture was stirred at 60° C. for 1 h. Then sat. aq. Na₂S₂O₃ (2 mL) was added and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide (SC_1129) (8 mg) as a white solid. [M+H]⁺538.3

Synthesis of SC_1136: CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide

50% Propylphosphonic anhydride (T3P) solution in EtOAc (0.766 mL, 1.204 mmol) was added to a solution of crude CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-994) (250 mg, 0.602 mmol), 2-(methylsulfonyl)ethanamine hydrochloride (115.4 mg, 0.723 mmol) and diisopropylethylamine (0.410 mL, 2.408 mmol) in DCM (15 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 4 h. The reaction mixture was quenched with water and the organic product was extracted with DCM (3×20 mL). The combined organic layer was washed with sat. aq. NaHCO₃ (10 mL), brine (10 mL) and dried over anhydr. Na₂SO₄ and concentrated under reduced pressure The crude product was purified by preparative HPLC to give 56 mg (25%) of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide (SC_1136) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.62). [M+H]⁺521.3

Synthesis of SC_1138: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide

CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide (SC_1120) (22 mg) was dissolved in a water/methanol (500 μL/500 μL) and oxone (39 mg) was added. The resulting mixture was stirred at RT for 18 h. Then 2N aq. NaOH (2 mL) was added and the aqueous layer was extracted with DCM (3×5mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide (SC_1138) (14 mg) as a white solid. [M+H]⁺554.3

Synthesis of SC_1149: CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide

CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (0.2 g, 0.57 mmol) was added to a solution of NaH (60% in mineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and 2-bromo-N-methylacetamide (0.52 g, 3.47 mmol) in DMF (2 mL) was added dropwise. the resulting mixture was stirred for 30 min at 0° C. and then at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Cl and the organic product was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purified of the crude product by preparative TLC using 5% MeOH in DCM as a mobile phase gave 45 g (18%) of CIS -2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide (SC_1149) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3). [M+H]⁺417.3

Synthesis of SC_1303: CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide

N-Iodosuccinimide (71.8 mg, 0.319 mmol) was added to a solution of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1301) (100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 5 mL) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N NaOH solution to pH ˜10 and the organic product was extracted with ethyl acetate (10 mL×3). The combined organic extracts were dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. The resulting crude product was purified by preparative reverse phase HPLC to give 50 mg of the desired product as a formiate. The isolated product was diluted with water (5 mL) and basified with sat. aq. NaHCO₃. The product was extracted with EtOAc (10 mL×2), combined organic layer was dried over anhydr. Na₂SO₄ and concentrated in vacuo to yield 42 mg (43%) of CIS-2-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1303) as an off-white solid (TLC system: 5% MeOH in DCM; R_(f): 0.42.). [M+H]⁺457.3

Synthesis of SC_1308: CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one

50 wt % solution of T3P (2.32 g, 3.65 mmol) in EtOAc was added to a suspension of CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetic acid hydrochlorid (INT-995) (600 mg, 1.46 mmol), thiomorpholin-1,1-dioxide (237 mg, 1.76 mmol) and diisopropylethylamine (1.27 mL, 7.30 mmol) in THF (10 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with water, the organic product was extracted with EtOAc (3×25mL). The combined organic extracts were washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude compound. Purification by flash silica column chromatography using 4-5% methanol in DCM as eluent yielded 250 mg (34%) of CIS-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one (SC_1308) as a solid (TLC system: 10% MeOH in DCM R_(f): 0.30). [M+H]⁺491.3

Synthesis of SC_1324: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

The suspension of TFA salt of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (500 mg, 1.12 mmol, 1.0 eq.) in THF (40 ml) was cooled to 0° C. and DIPEA (0.78 ml, 4.48 mmol, 4.0 eq.), 1-hydroxy-1H-benzotriazole ammonium salt (287 mg, 1.68 mmol, 1.5 eq.) and EDCl (321 mg, 1.68 mmol, 1.5 eq.) were sequentially added. The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. Crude product was purified by column chromatography (neutral alumina; 0.5% NH₃ in 20% MeOH/DCM) to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (SC_1324) (250 mg, 0.75 mmol, 67%) as an off-white solid. [M+H]⁺331.2

Synthesis of SC_1332: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide

KOtBu (1M in THF) (1.4 mL, 1.37 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (250 mg, 0.915 mmol) in THF (15 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 30 min 2-Bromo-N-phenylacetamide (312 mg, 1.46 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 4 h. Sat. aq. NH₄Cl (10 mL) was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 60 mg (16%) of CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide (SC_1332) as a white solid. ¹H NMR (CDCl₃): δ 8.32 (br s, 1H), 7.50-7.48 (d, 2H), 7.39-7.36 (m, 2H), 7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90 (br s, 1H), 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94-1.91 (m, 2H),1.58-1.53 (m, 2H). [M+H]⁺407.2

Synthesis of SC-1346: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester

KOtBu (187 mg, 1.67 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-di azaspiro[4.5]decan-2-one (INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL) at 0° C. The mixture was stirred for 15 min at this temperature and t-butyl-bromoacetate (0.246 mL, 1.67 mmol) was added subsequently. After stirring for 1 h at 0° C., the reaction was quenched with water, diluted with EtOAc and stirred for 5 min at RT. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 0.5 M NH₃ in MeOH/DCM gradient) to yield 395 mg (75%) of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) as a white solid. ¹H NMR (600 MHz, DMSO) δ 7.43-7.36 (m, 1H), 7.17 (d, 1H), 7.13 (dt, 1H), 7.09 (td, 1H), 3.75 (d, 2H), 3.21 (s, 2H), 3.05 (d, 2H), 2.67-2.61 (m, 2H), 2.08-2.00 (m, 2H), 1.99 (d, 7H), 1.98-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.39 (d, 8H), 1.38-1.29 (m, 5H). [M+H]⁺474.3

of SC-1357: TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-morpholino-2-oxoethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution of TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid trifluoroacetate (300 mg, 0.6 mmol, 1.0 eq.) in DCM (10 mL) were added DIPEA (0.62 mL, 3.6 mmol, 6.0 eq.) and HATU (296 mg, 0.78 mmol, 1.3 eq.) followed by morpholine (102 mg, 1.08 mmol, 1.8 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with water (25 mL) and extracted with DCM (50 mL×2). Combined organic layer was washed with brine (25 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting crude product was purified by prep HPLC to get TRANS-1-cyclopropylmethyl-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC-1357) (55 mg, 0.12 mmol, 20%) as a white solid. ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.44-7.29 (m, 5H), 3.96 (s, 2H), 3.56 (bs, 4H), 3.42-3.40 (m, 4H), 3.29 (s, 2H), 2.67 (bs, 2H), 2.55-2.54 (d, 2H, J=6.36 Hz), 1.92 (s, 6H), 1.56-0.144 (m, 6H), 0.51-0.48 (m, 1H), 0.16-0.14 (m, 2H), (−0.26)-(−0.27) (m, 2H). [M+H]⁺455.1

Synthesis of INT-1363: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

Step 1: tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

In analogy to the method described for INT-1019 step 1 TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1061) was converted into tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate. LC-MS: m/z [M+H]⁺=442.3

Step 2: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide (INT-1363)

A mixture of TRANS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (250 mg, 0.56 mmol, 1.0 eq.) and 7M NH₃ in MeOH (5 mL) was heated in sealed tube at 90° C. for 16 h, then cooled down to RT and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel basified with aq. NH₃; 10% MeOH in DCM) to yield 2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (77 mg,0.2 mmol, 35%) as a white solid. LC-MS: m/z [M+1]⁺=385.2 (MW calc. 384.52); ¹H NMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm)=7.40-7.29 (m, 5H), 6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 2.61-2.60 (m, 4H), 2.00 (s, 6H), 1.61-0.153 (m, 6H), 0.58-0.56 (m, 1H), 0.22-0.20 (m, 2H), (−0.16)-(−0.18) (m, 2H).

For further exemplary compounds the last synthesis step in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.

in analogy m/z Example Chemical Name Reactant I Reactant II to method [M + H]⁺ SC_1001 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5 8-dimethylamino-2-oxo-8- heptaoxadocosan- phenyl-1,3- 22-amine diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1002 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3 methyl)-8-dimethylamino-2- 6-aminopicolinate oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-2- carboxylic acid methyl ester SC_1003 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (R)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1R)-2-hydroxy-1-methyl- ethyl]-acetamide SC_1004 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (S)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1S)-2-hydroxy-1-methyl- ethyl]-acetamide SC_1005 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-methyl-2- SC_1308 484.3 8-dimethylamino-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1006 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl 6-aminonicotinate SC_1308 534.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-nicotinic acid methyl ester SC_1007 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-methyl-2- SC_1308 498.3 methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-2- methyl-propionamide SC_1008 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,2- SC_1308 498.3 methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,2-dimethyl- propionamide SC_1009 CIS-2-[[2-[1-(Cyclobutyl- INT 993 N,2-dimethyl-2- SC_1308 512.4 methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-N,2- dimethyl-propionamide SC_1010 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N,N-dimethyl-2- SC_1308 498.3 8-dimethylamino-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(dimethyl-carbamoyl)-methyl]- N-methyl-acetamide SC_1011 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-2- SC_1308 484.3 methyl)-8-dimethylamino-2- methylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamide SC_1012 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyridin-2-yl)- acetamide SC_1013 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1014 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin- SC_1308 506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1015 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3 methyl)-8-dimethylamino-2- methylpicolinamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- pyridine-2-carboxylic acid amide SC_1016 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cis-3- SC_1308 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1017 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 trans-3- SC_1308 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1018 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1308 469.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclopropanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopropyl)- methyl]-acetamide SC_1019 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-amino-1- SC_1308 540.3 8-dimethylamino-2-oxo-8- morpholinopropan-1-one phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-morpholin-4-yl-3-oxo- propyl)-acetamide SC_1020 CIS-N-(1-Cyano-cyclopropyl)- INT 993 1- SC_1308 464.3 2-[1-(cyclobutyl-methyl)-8- aminocyclopropanecarbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1021 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3- SC_1308 497.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)- methyl]-acetamide SC_1022 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1R)-2- SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]- acetamide SC_1030 CIS-N-(4-Cyano-pyridin-2-yl)- INT 993 2-aminoisonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1031 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-2- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-2-yl)- acetamide SC_1032 CIS-2-[[2-[1-(Cyclobutyl- INT 993 methyl 2-aminoisonicotinate SC_1308 534.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-isonicotinic acid methyl ester SC_1033 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyridin-4-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyridin-4-yl)- acetamide SC_1034 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-fluoropyridin-3-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-fluoro-pyridin-3-yl)- acetamide SC_1035 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyrimidin-5-amine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyrimidin-5-yl)- acetamide SC_1036 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyrimidin-2-amine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-pyrimidin-2-yl)- acetamide SC_1037 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin-2-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-fluoro-pyridin-2-yl)- acetamide SC_1038 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin-4-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-fluoro-pyridin-4-yl)- acetamide SC_1039 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin-3-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-3-yl)- acetamide SC_1040 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-3-yl)- acetamide SC_1041 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-3-yl)- acetamide SC_1042 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin-4-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-4-yl)- acetamide SC_1043 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-3-yl)- acetamide SC_1044 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-fluoropyridin-2-amine SC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-fluoro-pyridin-2-yl)- acetamide SC_1045 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-pyridin-2-yl)- acetamide SC_1046 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-2-yl)- acetamide SC_1047 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-2-yl)- acetamide SC_1048 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methoxypyridin-4-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methoxy-pyridin-4-yl)- acetamide SC_1049 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridazin-3- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridazin-3-yl)- acetamide SC_1050 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylsulfonyl)pyridin- SC_1051 554.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methylsulfonyl-pyridin-2-yl)- acetamide SC_1052 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylsulfonyl)pyridin- SC_1051 554.3 8-dimethylamino-2-oxo-8- 3-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfonyl-pyridin-3-yl)- acetamide SC_1053 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrazin-2-amine SC_1051 507.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrazin-2-yl)- acetamide SC_1054 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin-2-amine SC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1055 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamide SC_1056 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-5-ylmethanamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-5-yl-methyl)-acetamide SC_1057 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-2-ylmethanamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-2-yl-methyl)-acetamide SC_1058 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)-piperidine-3,4-diol SC_1051 499.3 [2-[(3S,4S)-3,4-dihydroxy- piperidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1059 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4S)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1060 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1061 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cyclopropanamine SC_1051 439.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- cyclopropyl-acetamide SC_1062 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(methylamino)ethanol SC_1051 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-N-methyl- acetamide SC_1063 CIS-1-(Cyclobutyl-methyl)-8- INT 993 piperidin-3-ol SC_1051 483.3 dimethylamino-3-[2-(3- hydroxy-piperidin-1-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1064 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1051 483.3 8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclobutyl)- methyl]-acetamide SC_1065 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1051 484.3 methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- acetamide SC_1066 CIS-1-(Cyclobutyl-methyl)-8- INT 993 5,6,7,8-tetrahydro- SC_1051 506.3 dimethylamino-3-[2-oxo-2- [1,2,4]triazolo[1,5- (5,6,7,8-tetrahydro- a]pyrazine [1,2,4]triazolo[1,5-a]pyrazin-7- yl)-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1067 CIS-3-[[2-[1-(Cyclobutyl- INT 993 3-amino-N,N- SC_1051 498.3 methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- propionamide SC_1068 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20,23-octa- SC_1308 765.5 8-dimethylamino-2-oxo-8- oxapentacosan-25-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-[2-(2- methoxy-ethoxy)-ethoxy]- ethoxy]-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]- acetamide SC_1069 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-5- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-5-yl)- acetamide SC_1070 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-5- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-5-yl)- acetamide SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)- INT 993 6-aminonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1074 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-4-yl)- acetamide SC_1075 CIS-N-(2-Cyano-pyrimidin-5- INT 993 5-aminopyrimidine-2- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1077 CIS-N-(3-Cyano-pyridin-2-yl)- INT 993 2-aminonicotinonitrile SC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1078 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1079 CIS-6-[[2-[1-(Cyclobutyl- SC 1072 — SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-3- carboxylic acid amide SC_1080 CIS-N-(4-Cyano-pyrimidin-2- INT 993 2-aminopyrimidine-4- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1081 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1,3,4-thiadiazol-2-amine SC_1051 483.2 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- ([1,3,4]thiadiazol-2-yl)- acetamide SC_1082 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 thiazol-2-amine SC_1051 482.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- thiazol-2-yl-acetamide SC_1083 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylisoxazol-3-amine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-isoxazol-3-yl)- acetamide SC_1084 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 isoxazol-3-amine SC_1051 466.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- isoxazol-3-yl-acetamide SC_1085 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-methyl-1H-pyrazol-3- SC_1051 479.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1-methyl-1H-pyrazol-3-yl)- acetamide SC_1086 CIS-N-(4-Cyano-5- INT 993 3-amino-5-(methylthio)-1H- SC_1051 536.3 methylsulfanyl-1H-pyrazol-3- pyrazole-4-carbonitrile yl)-2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1087 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrazin-2-amine SC_1051 507.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrazin-2-yl)- acetamide SC_1088 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyridazin-4-yl-methyl)- acetamide SC_1089 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(aminomethyl)phenol SC_1051 505.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-hydroxyphenyl)-methyl]- acetamide SC_1090 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1-methyl-1H-imidazol-4- SC_1051 493.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-methyl-1H-imidazol-4-yl)- methyl]-acetamide SC_1091 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methylpyridin-3- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methyl-pyridin-3-yl)- methyl]-acetamide SC_1092 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-2-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-2-yl-methyl)- acetamide SC_1093 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyridazin-3-yl-methyl)-acetamide SC_1094 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)- acetamide SC_1095 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrazin-2-ylmethanamine SC_1051 491.3 8-dimediylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrazin-2-yl-methyl)-acetamide SC_1096 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-4-ylmedianamine SC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-4-yl-methyl)-acetamide SC_1097 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methylpyridin-3- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methyl-pyridin-3-yl)- methyl]-acetamide SC_1098 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyridin-3- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxy-pyridin-3-yl)- methyl]-acetamide SC_1099 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyridin-3- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methoxy-pyridin-3-yl)- methyl]-acetamide SC_1100 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methylpyridin-2- SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(6-methyl-pyridin-2-yl)- methyl]-acetamide SC_1101 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methoxypyridin-2- SC_1051 520.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(6-methoxy-pyridin-2-yl)- methyl]-acetamide SC_1102 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2- SC_1051 519.3 8-dimethylamino-2-oxo-8- methoxyphenyl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxyphenyl)-methyl]- acetamide SC_1103 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 o-tolylmethanamine SC_1051 503.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (o-tolyl-methyl)-acetamide SC_1104 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3 methyl)-8-dimethylamino-2- methylnicotinamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- pyridine-3-carboxylic acid amide SC_1105 CIS-2-[[2-[1-(Cyclobutyl- SC 1030 — SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-4- carboxylic acid amide SC_1106 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)- acetamide SC_1107 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-4-yl)- acetamide SC_1109 CIS-2-[1-(Cyclobutyl-methyl)- SC 1069 SC_1110 493.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-hydroxy-pyrimidin-5-yl)- acetamide SC_1111 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-3-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-hydroxy-pyridin-2-yl)- acetamide SC_1112 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-aminotetrahydro-2H- SC_1308 531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1113 CIS-1-(Cyclobutyl-methyl)-8- INT 993 thiomorpholine 1,1-dioxide SC_1308 517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1114 CIS-2-[8-Dimethylamino-1-(2- INT 997 pyrimidin-4-amine SC_1308 467.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-pyrimidin-4-yl-acetamide SC_1115 CIS-2-[8-Dimethylamino-1-(2- INT 997 methylamine SC_1308 403.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1117 CIS-N-(5-Cyano-pyrimidin-4- INT 993 4-aminopyrimidine-5- SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1118 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylthio)pyridin-2- SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methylsulfanyl-pyridin-2-yl)- acetamide SC_1119 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2- SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamide SC_1120 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylthio)pyridin-2- SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfanyl-pyridin-2-yl)- acetamide SC_1121 CIS-2-[8-Dimethylamino-1-(2- INT 997 2-aminoethanol SC_1308 433.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1122 CIS-2-[[2-[8-Dimethylamino-1- INT 997 2-aminoacetamide SC_1308 446.3 (2-methoxy-ethyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1123 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 methylamine SC_1308 413.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1124 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminoethanol SC_1308 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1125 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-2-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-hydroxy-pyridin-2-yl)- acetamide SC_1126 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyrimidin-5- SC_1308 521.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxy-pyrimidin-5-yl)- methyl]-acetamide SC_1127 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyrimidin-2- SC_1308 521.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-methoxy-pyrimidin-2-yl)- methyl]-acetamide SC_1130 CIS-2-[[2-[1-(Cyclobutyl- SC 1011 2-amino-2- SC_1303 470.3 methyl)-8-methylamino-2-oxo- methylpropanamide 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamidc SC_1131 CIS-2-[[2-[1-(Cyclobutyl- SC 1222 — SC_1303 456.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1132 CIS-2-[[2-[1-(Cyclobutyl- SC 1078 — SC_1303 442.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1133 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-(2- SC_1308 545.4 8-dimethylamino-2-oxo-8- methoxyethoxy)ethoxy)- phenyl-1,3- ethanamine diazaspiro[4.5]decan-3-yl]-N- [2-[2-(2-methoxy-ethoxy)- ethoxy]-ethyl]-acetamide SC_1134 CIS-N-(Carbamoyl-methyl)-2- SC 1146 2-(methylamino)acetamide SC_1303 456.3 [1-(cyclobutyl-methyl)-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1135 CIS-2-[1-(Cyclobutyl-methyl)- SC 1005 N-methyl-2- SC_1303 470.3 8-methylamino-2-oxo-8-phenyl- (methylamino)acetamide 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1137 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyrimidin-5-amine SC_1136 493.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1139 CIS-2-[8-Dimethylamino-1- INT 996 2-aminoethanol SC_1308 460.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1140 CIS-2-[[2-[1-(Cyclobutyl- SC 1007 — SC_1303 484.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-2- methyl-propionamide SC_1141 CIS-1-(Cyclobutyl-methyl)-3- SC 1214 — SC_1303 503.3 [2-(1,1-dioxo-[1,4]thiazinan-4- yl)-2-oxo-ethyl]-8- methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1142 CIS-2-[1-(Cyclobutyl-methyl)- SC 1199 — SC_1303 707.5 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-[2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1143 CIS-2-[[2-[1-(Cyclobutyl- SC 1065 — SC_1303 470.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- acetamide SC_1144 CIS-2-[1-(Cyclobutyl-methyl)- SC 1070 — SC_1110 493.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-hydroxy-pyrimidin-2-yl)- acetamide SC_1145 CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1138 554.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methylsulfonyl-pyridin-2-yl)- acetamide SC_1146 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3 methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1147 CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308 470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1148 CIS-2-(8-Dimethylamino-2- INT 995 methylamine SC_1136 387.3 oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)-N- methyl-acetamide SC_1150 CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1129 538.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [4-(methylsulfinyl)-pyridin-2- yl]-acetamide SC_1151 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminopyridin-3-ol SC_1308 492.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-hydroxy-pyridin-2-yl)- acetamide SC_1152 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2- SC_1308 505.3 8-dimethylamino-2-oxo-8- (methylsulfonyl)ethanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamide SC_1154 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)-pyrrolidine-3,4-diol SC_1308 485.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1155 CIS-2-[1-(Cyclobutyl-methyl)- SC 1198 — SC_1303 429.3 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1156 CIS-2-[8-Dimethylamino-1- INT 996 pyrimidin-4-amine SC_1308 494.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1157 CIS-2-[8-Dimethylamino-1- INT 996 methylamine SC_1308 430.3 [(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1158 CIS-2-[[2-[8-Dimethylamino-1- INT 992 2-aminoacetamide SC_1136 444.3 (2-methyl-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1159 CIS-2-[8-Dimethylamino-1-[(1- INT 994 NH₄Cl SC_1136 415.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1160 CIS-2-[8-Dimethylamino-1-[(1- INT 994 methylamine SC_1136 429.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1161 CIS-2-[[2-[8-Dimethylamino-1- INT 987 N-(2-amino-2-oxoethyl)-2- SC_1149 460.3 (3-methoxy-propyl)-2-oxo-8- bromoacetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1162 CIS-2-[8-Dimethylamino-1-(2- INT 984 2-bromo-N- SC_1149 401.3 methyl-propyl)-2-oxo-8-phenyl- methylacetamide 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1163 CIS-1-(Cyclobutyl-methyl)-3- SC 1154 — SC_1303 471.3 [2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8- methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1164 CIS-2-[8-Dimethylamino-1-[(1- INT 998 methylamine SC_1308 427.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1165 CIS-2-[8-Dimethylamino-1-[(1- INT 998 pyrimidin-4-amine SC_1308 491.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1166 CIS-2-[[2-[8-Dimethylamino-1- INT 998 2-aminoacetamide SC_1308 470.3 [(1-methyl-cyclobutyl)-methyl]- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1167 CIS-2-[8-Dimethylamino-1-[(1- INT 998 2-aminoethanol SC_1308 457.3 methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1168 CIS-2-[[2-[1-(Cyclopropyl- INT 983 N-(2-amino-2-oxoethyl)-2- SC_1149 442.3 methyl)-8-dimethylamino-2- bromoacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1169 CIS-2-[1-(Cyclobutyl-methyl)- INT 986 2-bromo-N- SC_1149 427.3 8-(ethyl-methyl-amino)-2-oxo- methylacetamide 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1171 CIS-2-[[2-(8-Dimethylamino-2- INT 995 2-aminoacetamide SC_1308 430.3 oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)- acetyl]amino]-acetamide SC_1172 CIS-2-[[2-[8-Dimethylamino-1- INT 994 2-aminoacetamide SC_1308 472.3 [(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1173 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-aminoethanol SC_1308 459.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1174 CIS-2-[8-Dimethylamino-1-[(1- INT 994 4-aminotetrahydro-2H- SC_1308 547.3 hydroxy-cyclobutyl)-methyl]-2- thiopyran 1,1-dioxide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1175 CIS-2-[1-(Cyclopropyl-methyl)- INT 983 2-bromo-N- SC_1149 399.3 8-dimethylamino-2-oxo-8- methylacetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1176 CIS-2-[1-[(1-Cyano- INT 951 2-bromo-N- SC_1149 438.3 cyclobutyl)-methyl]-8- methylacetamide dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1177 CIS-2-[1-(Cyclobutyl-methyl)- INT 998 2-aminoethanol SC_1308 457.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1178 CIS-2-[[2-[1-(Cyclobutyl- INT 998 2-aminoacetamide SC_1308 470.3 methyl)-8-(ethyl-methyl- amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1179 CIS-2-[[2-[1-(Cyclobutyl- SC 1008 — SC_1303 484.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,2-dimethyl- propionamide SC_1180 CIS-2-[8-Dimethylamino-1-(3- INT 990 2-aminoethanol SC_1308 447.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1181 CIS-2-[8-Dimethylamino-1-(3- INT 990 N-methyl-2- SC_1308 488.3 methoxy-propyl)-2-oxo-8- (methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1182 CIS-8-Dimethylamino-1-(3- INT 990 piperazin-2-one SC_1308 486.3 methoxy-propyl)-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8- phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1183 CIS-N-(Carbamoyl-methyl)-2- INT 990 2-(methylamino)acetamide SC_1308 474.3 [8-dimethylamino-1-(3- methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1184 CIS-2-[8-Dimethylamino-1-(3- INT 990 cis-3- SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- |(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1185 CIS-2-[8-Dimethylamino-1-(3- INT 990 trans-3- SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1186 CIS-2-[8-Dimethylamino-1-(3- INT 990 3- SC_1073 501.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)- methyl]-acetamide SC_1187 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyridazin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1188 CIS-2-[8-Dimethylamino-1-(3- INT 990 6-methoxypyridin-2-amine SC_1308 510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1189 CIS-N-(2-Cyanoethyl)-2-[8- INT 990 3-aminopropanenitrile SC_1308 456.3 dimethylamino-1-(3-methoxy- propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1190 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-5-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1191 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1192 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 6-methoxypyridin-2-amine SC_1073 520.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamide SC_1193 CIS-2-[8-Dimediylamino-1-[(1- INT 995 pyridin-3-amine SC_1308 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-3-yl-acetamide SC_1195 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 NH₄Cl SC_1073 399.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamide SC_1196 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 pyrimidin-4-amine SC_1073 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1197 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-methoxyethanamine SC_1073 457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-ethyl)-acetamide SC_1198 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-aminoethanol SC_1073 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1199 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5 8-dimethylamino-2-oxo-8- heptaoxadocosan-22-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1201 CIS-2-[1-(Cyclobutyl-methyl)- SC 1229 — SC_1303 399.3 8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl- INT 993 (S)-pyrrolidine-2- SC_1308 496.3 methyl)-8-dimethylamino-2- carboxamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]-pyrrolidine-2-carboxylie acid amide SC_1204 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1308 484.3 methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N.N-dimethyl- acetamide SC_1205 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxetan-3-amine SC_1308 455.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxetan-3-yl)-acetamide SC_1206 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1207 CIS-1-(Cyclobutyl-methyl)-8- INT 999 piperazin-2-one SC-1073 482.3 dimethylamino-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8- phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1208 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-aminotetrahydro-2H- SC_1073 531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1209 CIS-1-(Cyclobutyl-methyl)-8- INT 999 morpholin-2-ylmethanol SC_1073 499.3 dimethylamino-3-[2-[2- (hydroxymethyl)-morpholin-4- yl]-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1210 CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308 470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1211 CIS-N-(Cyano-methyl)-2-[1- INT 993 2-aminoacetonitrile SC_1308 438.3 (cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1212 CIS-N-(2-Acetylamino-ethyl)-2- INT 993 N-(2-aminoethyl)acetamide SC_1308 484.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1213 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-(methylsulfonyl)ethan- SC_1073 505.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamide SC_1214 CIS-1-(Cyclobutyl-methyl)-8- INT 999 thiomorpholine 1,1-dioxide SC_1073 517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1215 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-(aminomethyl)tetra- SC_1073 545.3 8-dimethylamino-2-oxo-8- hydro-2H-thiopyran 1,1- phenyl-1,3- dioxide diazaspiro[4.5]decan-3-yl]-N- [(1,1-dioxo-thian-4-yl)-methyl]- acetamide SC_1216 CIS-1-(Cyclobutyl-methyl)-8- INT 999 1-(methylsulfonyl)- SC_1073 546.3 dimethylamino-3-[2-(4- piperazine methylsulfonyl-piperazin-1-yl)- 2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1217 CIS-N-(2-Cyanoethyl)-2-[1- INT 993 3-aminopropanenitrile SC_1308 452.3 (cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1218 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-amino-2-methylpropan-2- SC_1308 471.3 8-dimethylamino-2-oxo-8- ol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-2-methyl-propyl)- acetamide SC_1219 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-amino-1- SC_1308 526.3 8-dimethylamino-2-oxo-8- morpholinoethanone phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-morpholin-4-yl-2-oxo-ethyl)- acetamide SC_1220 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-aminoethoxy)ethanol SC_1308 487.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(2-hydroxy-ethoxy)-ethyl]- acetamide SC_1222 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3 methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1223 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-(2-aminoethyl)- SC_1308 520.3 8-dimethylamino-2-oxo-8- methanesulfonamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(methanesulfonamido)- ethyl]-acetamide SC_1224 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-(aminomethyl)- SC_1308 497.3 8-dimethylamino-2-oxo-8- cyclopentanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopentyl)- methyl]-acetamide SC_1225 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4- SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-hydroxy-cyclohexyl)- methyl]-acetamide SC_1226 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-methoxyethoxy)- SC_1308 501.3 8-dimethylamino-2-oxo-8- ethanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(2-methoxy-ethoxy)-ethyl]- acetamide SC_1227 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N¹,N¹-dimethylethane-1,2- SC_1308 470.3 8-dimethylamino-2-oxo-8- diamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(dimethylamino)ethyl]- acetamide SC_1228 CIS-2-[1-(Cyclobutyl-methyl)- INT 953 2-bromo-N- SC_1149 455.3 8-[methyl-(2-methyl-propyl)- methylacetamide amino]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1229 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 methylamine SC_1073 413.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1230 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1231 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-2-yl)- acetamide SC_1232 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-3-yl-acetamide SC_1233 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-5-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1234 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1235 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin-4- SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)- acetamide SC_1236 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin-4-amine SC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-4-yl)- acetamide SC_1300 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyridin-4-amine SC_1308 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-4-yl-acetamide SC_1301 CIS-2-[8-Dimethylamino-1-[(1- INT 994 oxetan-3-amine SC_1308 471.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxetan-3-yl)-acetamide SC_1302 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-methoxyethanamine SC_1308 473.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-ethyl)-acetamide SC_1304 CIS-2-[1-[(1-Hydroxy- SC 1301 — SC_1303 459.3 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-(2-methoxy-ethyl)-acetamide SC_1305 CIS-2-[8-Dimethylamino-1-(3- SC 1302 — SC_1308 510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamide SC_1306 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-ylmethanamine SC_1073 495.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)- acetamide SC_1309 CIS-2-[8-Dimethylamino-1-[(1- SC 1159 — SC_1128 492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1310 CIS-2-[1-[(1-Cyano- INT 989 NH₄Cl SC_1308 424.3 cyclobutyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1311 CIS-2-[[2-[1-[(1-Cyano- INT 989 2-aminoacetamide SC_1308 481.3 cyclobutyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1312 CIS-2-[1-[(1-Hydroxy- SC 1160 — SC_1303 415.3 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1313 CIS-3-[2-(1,1-Dioxo- SC 1308 — SC_1303 477.2 [1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-methylamino-8-phenyl- 1-propyl-1,3- diazaspiro[4.5]decan-2-one SC_1317 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridin-2-amine SC_1051 476.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1318 CIS-8-Dimethylamino-1-[(1- INT 994 morpholine SC_1136 485.3 hydroxy-cyclobutyl)-methyl]-3- (2-morpholin-4-yl-2-oxo-ethyl)- 8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1319 CIS-2-[1-[(1-Hydroxy- SC 1159 — SC_1303 401.2 cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1320 CIS-1-(Cyclobutyl-methyl)-8- INT 993 morpholine SC_1308 469.3 dimethylamino-3-(2-morpholin- 4-yl-2-oxo-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1321 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-(methylthio)pyridin-2- SC_1073 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methylsulfanyl-pyridin-2-yl)- acetamide

in analogy ¹H NMR m/z Example Chemical name Reactant I Reactant II to method data (M + H)⁺ SC_1322 CIS-3-[2-(1,1- INT-1014 thiomorpholin- SC_1308 ¹HNMR (DMSO-d6, 400 435.3 Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.40 (d, [1,4]thiazinan-4- SC_1303 2H, J = 7.2 Hz), yl)-2-oxo-ethyl]- (for step 2) 7.31 (t, 2H, J = 7.44 Hz), 8-methylamino-8- 7.18 (t, 1H, J = 6.78 Hz), phenyl-1,3- 6.61 (bs, 1H), 3.98 (s, diazaspiro[4.5]decan- 2H), 3.82 (bs, 4H), 2-one 3.21 (bs, 4H), 3.09 (s, 2H), 1.95 (t, 2H, J = 11.74 Hz), 1.85 (bs, 5H), 1.65 (bs, 2H), 1.48 (bs, 2H). SC_1323 CIS-2-(8- SC_1324 SC_1303 ¹HNMR (DMSO-d6, 317.2 Methylamino-2- 400 MHz), δ (ppm) = oxo-8-phenyl-1,3- 7.41 (d, diazaspiro[4.5]decan- 2H, J = 7.60 Hz), 7.30 (t, 3-yl)-acetamide 2H, J = 7.60 Hz), 7.23 (s, 1H), 7.18 (t, 1H, J = 7.08 Hz), 6.95 (s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.21 (s, 2H), 1.96 − 1.80 (m, 7H), 1.69 − 1.66 (m, 2H), 1.47 (d, 2H, J = 11.76 Hz). SC_1324 CIS-2-(8- INT-1014 procedure — 331.2 Dimethylamino-2- described oxo-8-phenyl-1,3- diazaspiro[4.5]decan- 3-yl)-acetamide SC_1325 CIS-3-[2-(1,1- INT-1015 thiomorpholin- SC_1308 ¹HNMR (DMSO-d6, 400 449.4 Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.42 (d, [1,4]thiazinan-4 SC_1303 2H, J = 7.2 Hz), 7.29 (t, 2H, yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.17 (t, 1H), 8-ethylamino-8- 6.61 (s, 1H), 5.75 (s, 1H), phenyl-1,3- 3.98 (s, 2H), 3.82 (s, 4H), diazaspiro[4.5]decan- 3.21 (s, 4H), 3.09 (s, 2H), 2-one 2.07 − 1.93 (m, 4H), 1.87 − 1.83 (m, 2H), 1.69 − 1.66 (m, 2H), 1.48 − 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1326 TRANS-3-[2- INT-1017 thiomorpholin- SC_1308 ¹HNMR (DMSO-d6, 400 449.2 (1,1-Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.50 (d, [1,4]thiazinan-4- SC_1303 2H, J = 7.4 Hz), 7.30 (t 2H, yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.18 − 7.15 (m, 8-ethylamino-8- 2H), 4.00 (s, 2H), 3.84 (bs, phenyl-1,3- 4H), 3.24 (s, 2H), 3.19 (s, diazaspiro[4.5]decan- 2H), 3.11 (s, 2H), 2.07 − 2-one 1.44 (m, 11H), 0.91 (t, 3H, J = 6.6 Hz). SC_1327 CIS-2-[1- INT-998 methylamine SC_1308 ¹H NMR (DMSO-d6, δ 399.3 (Cyclobutyl- (step 1) (for step 1), 7.71 − 7.70 (m, 1H), 7.43 methyl)-8- SC_1303 (d, 2H), 7.30 (t, 2H), 7.18 (t, methylamino-2- (for step 2) 1H), 3.64 (s, 2H), 3.21 (s, oxo-8-phenyl-1,3- 2H), 3.08 (d, 2H), 2.57 − diazaspiro[4.5]decan- 2.54 (m, 4H), 2.25 (m, 1H), 3-yl]-N- 2.11-2.06 (m, 2H), 1.97 − methyl-acetamide 1.82 (m, 7H), 1.80 − 1.67 (m, 4H), 1.59 (m, 2H), 1.36 − 1.35 (m, 2H). SC_1328 CIS-2-(8- INT-1015 SC_1324 ¹HNMR (DMSO-d6, 400 331.1 Ethylamino-2- MHz) δ (ppm) = 7.43 (d, oxo-8-phenyl-1,3- 2H, J = 7.6 Hz), 7.29 (t, 2H, diazaspiro[4.5]decan- J = 7.2 Hz), 7.22 (s, 1H), 3-yl)-acetamide 7.17 (t, 1H, J = 6.8 Hz), 6.95 (s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.07 − 2.05 (m, 2H), 1.93 (t, 2H, J = 11.2), 1.85 − 1.82 (m, 2H), 1.69 − 1.67 (m, 2H,), 1.48 − 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1329 TRANS-2-(8- INT-1017 SC_1324 ¹HNMR (DMSO-d6, 400 331.2 Ethylamino-2- MHz) δ (ppm) = 7.49 (d, oxo-8-phenyl-1,3- 2H, J = 7.56 Hz), 7.29 (t, diazaspiro[4.5]decan- 2H, J = 7.66 Hz), 7.24 (s, 3-yl)-acetamide 1H), 7.16 (t, 1H), 7.24 Hz), 7.11 (bs, 1H), 6.98 (bs, 1H), 3.59 (s, 2H), 3.17 (s, 2H), 2.09 − 1.95 (m, 4H). SC_1330 CIS-2-(8- INT-1014 2- SC_1308 ¹HNMR (DMSO-d6, 400 389.2 Dimethylamino-2- (methylamino)- MHz at 100 0C.), δ (ppm) = oxo-8-phenyl-1,3- ethanol 7.34 − 7.23 (m, 5H), 6.41 diazaspiro[4.5]decan- (s, 1H), 4.4 (bs, 1H), 3.89 3-yl)-N-(2- (s, 2H), 3.53 − 3.52 (m, 2H), hydroxy-ethyl)-N- 3.34 (t, 2H, J = 5.56 Hz), methyl-acetamide 3.13 (s, 2H), 2.89 (s, 2H), 2.31 − 2.27 (m, 2H), 2.01 (s, 6H), 1.89 − 1.78 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1331 CIS-8- INT-1020 1,4-thiazinane SC_1308 ¹H NMR (600 MHz, 547.3 Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (qd, 4H), [2-(1,1-dioxo- 7.26 (tt, 1H), 4.40 (s, 2H), [1,4]thiazinan-4- 3.89 (dt, 4H), 3.26 (t, 2H), yl)-2-oxo-ethyl]- 3.11 (d, 2H), 2.64 − 2.58 1-[(1-hydroxy- (m, 2H), 2.45 (td, 2H), 2.14 cyclobutyl)- (tt, 2H), 2.03 (td, 2H), 1.98 methyl]-8-phenyl- (s, 6H), 1.97 − 1.88 (m, 1,3- 2H), 1.70 − 1.63 (m, 1H), diazaspiro[4.5]decane- 1.58 − 1.47 (m, 3H). 2,4-dione SC_1332 CIS-2-(8- INT-976 procedure ¹H NMR (CDCl3): δ 8.32 407.2 Dimethylamino-2- described (br s, 1H), 7.50 − 7.48 (d, oxo-8-phenyl-1,3- 2H), 7.39 − 7.36 (m, 2H), diazaspiro[4.5]decan- 7.33 − 7.26 (m, 5H), 7.12 − 3-yl)-N-phenyl- 7.08 (t, 1H), 5.90 (br s, 1H), acetamide 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94 − 1.91 (m, 2H), 1.58 − 1.53 (m, 2H). SC_1333 CIS-N- INT-991 2- SC_1308 ¹HNMR (DMSO-d6, 400 388.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[1- acetamide•HCl 7.34 − 7.23 (m, 5H), 6.85 (bs, (cyclopropyl- 2H), 3.94 (s, 2H), 3.88 (s, methyl)-8- 2H), 3.26 (s, 2H), 3.00 − 2.99 dimethylamino-2- (m, 2H), 2.95 (s, 3H), 2.61 oxo-8-phenyl-1,3- (d, 2H, J = 13.2 Hz), 2.22 (t, diazaspiro[4.5]decan- 2H, J = 12 Hz), 2.06 (s, 6H), 3-yl]-N-methyl- 1.47 − 1.38 (m, 4H), 0.98 (m, acetamide 1H), 0.48 (d, 2H, J = 7.6 Hz), 0.28 (d, 2H, 4.8 Hz). SC_1334 CIS-2-(8- INT-1018 2-Bromo-N- SC_1332 ¹H NMR (DMSO-d6): δ 421.2 Dimethylamino- phenylacetamide 10.19 (s, 1H), 8.80 (br s, 2,4-dioxo-8- 1H), 7.52 − 7.520 (d, 2H), phenyl-1,3- 7.42 − 7.34 (m, 4H), 7.31 − diazaspiro[4.5]decan- 7.27 (m, 3H), 7.06 − 7.02 3-yl)-N-phenyl- (t, 1H), 4.11 (s, 2H), 2.49 − acetamide 2.45 (m, 2H), 2.03 − 1.93 (m, 8H), 1.71 − 1.68 (m, 2H), 1.60 − 1.54 (m, 2H). SC_1335 CIS-2-[1- INT-998 NH₄Cl SC_1308 ¹H NMR (DMSO-d6): δ 399.3 (Cyclobutyl- 7.36 − 7.22 (m, 6H), 6.93 (br methyl)-8- s, 1H), 3.61 (s, 2H), 3.18 (s, dimethylamino-2- 2H), 3.04 (d, 2H), 2.66 − 2.63 oxo-8-phenyl-1,3- (m, 2H), 2.54 − 2.52 (m, 1H), diazaspiro[4.5]decan- 2.07 − 1.93 (m, 10H), 1.81 − 3-yl]-acetamide 1.67 (m, 4H), 1.39 − 1.29 (m, 4H). SC_1336 CIS-2-[8- INT-1019 2,5,8,11- SC_1308 ¹H NMR (DMSO-d6): δ 605.3 Dimethylamino-1- tetraoxatridecan- 7.37 − 7.33 (m, 2H), 7.28 − [(1-hydroxy- 13-amine 7.26 (m, 3H), 6.67 (t, 1H), cyclobutyl)- 6.31 (br, s, 1H), 3.83 (s, methyl]-2-oxo-8- 2H), 3.65 − 3.59 (m, 10H), phenyl-1,3- 3.55 − 3.52 (m, 4H), 3.46 − diazaspiro[4.5]decan- 3.42 (m, 2H), 3.37 (s, 5H), 3-yl]-N-[2-[2- 3.29 (s, 2H), 2.68 − 2.65 (m, [2-(2-methoxy- 2H), 2.20 − 2.06 (m, 12H), ethoxy)-ethoxy]- 1.78 − 1.71 (m, 1H), 1.59 − ethoxy]-ethyl]- 1.56 (m, 2H), 1.48 − 1.37 acetamide (m, 3H). SC_1337 CIS-3-[2-(1,1- SC_1331 SC_1303 ¹H NMR (600 MHz, 533.3 Dioxo- DMSO) δ 7.46 (d, 2H), 7.33 [1,4]thiazinan-4- (t, 2H), 7.21 (t, 1H), 4.42 (s, yl)-2-oxo-ethyl]- 2H), 3.90 (dt, 4H), 3.49 (s, 1-[(1-hydroxy- 2H), 3.28 (t, 2H), 3.12 (t, cyclobutyl)- 2H), 2.47 (dd, 2H), 2.35 − methyl]-8- 2.25 (m, 2H), 2.15 − 2.08 methylamino-8- (m, 2H), 1.98 − 1.89 (m, phenyl-1,3- 6H), 1.84 (d, 2H), 1.71 − diazaspiro[4.5]decane- 1.63 (m, 1H), 1.58 − 1.48 2,4-dione (m, 3H). SC_1338 CIS-2-(8- INT-976 2-bromo-N- SC_1332 ¹H NMR (DMSO-d6): δ 521.3 Dimethylamino-2- (2,5,8,11- 7.78 (t, 1H), 7.37 − 7.23 (m, oxo-8-phenyl-1,3- tetraoxatridecan- 5H), 6.89 (br s, 1H), 3.60 diazaspiro[4.5]decan- 13-yl)acetamide (s, 2H), 3.49 − 3.47 (m, 10H), 3-yl)-N-[2-[2- 3.43 − 3.37 (m, 4H), 3.22 − [2-(2-methoxy- 3.17 (m, 5H), 3.08 (s, 2H), ethoxy)-ethoxy]- 2.30 (br m, 2H), 1.92 − 1.74 ethoxy]-ethyl]- (m, 10H), 1.38 (br m, 2H). acetamide SC_1339 CIS-N- INT-1034 2- SC_1308 ¹HNMR (DMSO-d6, 400 388.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-N- acetamide•HCl 7.43 (d, 2H, J = 7.52 Hz), methyl-2-(8- 7.31 (t, 2H, J = 7.44 Hz), methylamino-2- 7.18 (t, 1H, J = 7.20 Hz), oxo-8-phenyl-1,3- 6.8 (bs, 2H), 3.88 (s, 4H), diazaspiro[4.5]decan- 3.25 (s, 2H), 2.95 (3H, 3-yl)-acetamide merged with DMSO water), 1.97 − 1.85 (m, 7H), 1.77 − 1.50 (m, 4H). SC_1340 CIS-N- INT-1014 2-methylamino- SC_1308 ¹HNMR (DMSO-d6, 400 402.1 (Carbamoyl- acetamide•HCl MHz at 100 0C.), δ (ppm) = methyl)-2-(8- 7.33 − 7.23 (m, 5H), 6.84 (bs, dimethylamino-2- 2H), 6.45 (s, 1H), 3.87 (s, oxo-8-phenyl-1,3- 4H), 3.13 (s, 2H), 2.95 (3H, diazaspiro[4.5]decan- merged with DMSO water), 3-yl)-N- 2.32 − 2.27 (m, 2H), 2.01 (s, methyl-acetamide 6H),1.88 − 1.77 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1341 CIS-N- INT-1035 2- SC_1308 ¹HNMR (DMSO-d6, 400 472.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[8- acetamide•HCl 7.33 − 7.24 (m, 5H), 6.8 (bs, dimethylamino-1- 2H), 4.63 (t, 2H, J = 5.6 (oxetan-3-yl- Hz), 4.39 (s, 2H), 3.93 − 3.87 methyl)-2-oxo-8- (m, 4H), 3.36 (d, 2H, J = 6.8 phenyl-1,3- Hz), 3.24 (m, 3H), 2.95 (s, diazaspiro[4.5]decan- 3H), 2.66 − 2.60 (m, 2H), 3-yl]-N- 2.06 − 2.03 (m, 8H), 1.44 − methyl-acetamide 1.37 (m, 4H). SC_1342 CIS-N-(2- INT-1034 2- SC_1308 ¹HNMR (DMSO-d6, 400 375.0 Hydroxy-ethyl)- (methylamino)- MHz at 100 0C.), δ (ppm) = N-methyl-2-(8- ethanol 7.41 (d, 2H, J = 7.48 Hz), methylamino-2- 7.31 (t, 2H, J = 7.60 Hz), oxo-8-phenyl-1,3- 7.18 (t, 1H), J = 7.18 Hz), diazaspiro[4.5]decan- 6.24 (s, 1H), 4.58 − 4.36 (m, 3-yl)-acetamide 1H), 3.92 (bs, 2H), 3.52 (bs, 2H), 3.34 (t, 2H, J = 5.72 Hz), 3.24 (s, 2H), 2.96 − 2.84 (m, 3H), 1.97 − 1.84 (m, 7H), 1.74 − 1.49 (m, 4H). SC_1343 CIS-2-[1- INT-991 ammonium SC_1308 ¹H NMR (DMSO d6): δ 385.3 (Cyclopropyl- chloride 7.34 − 7.25 (m, 6H), 6.96 (s, methyl)-8- 1H), 3.63 (s, 2H), 3.22 (m, dimethylamino-2- 2H), 2.93 (d, 2H), 2.67 − 2.64 oxo-8-phenyl-1,3- (m, 2H), 2.16 (t, 2H), 1.97 diazaspiro[4.5]decan- (s, 6H), 1.43 − 1.31 (m, 4H), 3-yl]-acetamide 0.93 (m, 1H), 0.46 − 0.45 (m, 2H), 0.26 (m, 2H). SC_1344 CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSO d6): δ 429.3 (Cyclopropyl- aminoethanol 7.77 − 7.75 (m, 1H), 7.36 − methyl)-8- 7.33 (m, 4H), 7.26 − 7.23 (m, dimethylamino-2- 1H), 4.65 − 4.63 (m, 1H), oxo-8-phenyl-1,3- 3.67 (s, 2H), 3.39 − 3.35 (m, diazaspiro[4.5]decan- 2H), 3.21 (s, 2H), 3.12 − 3.09 3-yl]-N-(2-hydroxy- (m, 2H), 2.94 − 2.93 (m, 2H), ethyl)-acetamide 2.67 − 2.64 (m, 2H), 2.19 − 2.14 (t, 2H), 1.97 (s, 6H), 1.42 − 1.31 (m, 4H), 0.93 − 0.92 (s, 1H), 0.48 − 0.44 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1345 CIS-2-[1- INT-1032 2- SC_1308 ¹H NMR (600 MHz, 475.3 (Cyclobutyl- (methylamino)- DMSO) δ 7.39 (td, 1H), methyl)-8- ethanol 7.16 (dd, 1H), 7.13 (dt, 2H), dimethylamino-8- 7.08 (td, 1H), 3.99 (s, 1H), (3-fluorophenyl)- 3.91 (s, 1H), 3.52 (q, 1H), 2-oxo-1,3- 3.45 (d, 1H), 3.40 − 3.36 diazaspiro[4.5]decan- (m, 0H), 3.34 − 3.28 (m, 3-yl]-N-(2- 2H), 3.19 (d, 2H), 3.05 (dd, hydroxy-ethyl)-N- 2H), 2.96 (s, 2H), 2.80 (s, methyl-acetamide 2H), 2.66 − 2.60 (m, 3H), 2.07 − 1.93 (m, 3H), 1.99 (s, 7H), 1.85 − 1.74 (m, 2H), 1.75 − 1.65 (m, 3H), 1.40 − 1.28 (m, 5H). SC_1346 CIS-2-[1- INT-1031 tert-butyl- procedure ¹H NMR (600 MHz, 474.3 (Cyclobutyl- bromo acetate described DMSO) δ 7.43 − 7.36 (m, methyl)-8- 1H), 7.17 (d, 1H), 7.13 (dt, dimethylamino-8- 1H), 7.09 (td, 1H), 3.75 (d, (3-fluorophenyl)- 2H), 3.21 (s, 2H), 3.05 (d, 2-oxo-1,3- 2H), 2.67 − 2.61 (m, 2H), diazaspiro[4.5]decan- 2.08 − 2.00 (m, 2H), 1.99 3-yl]-acetic (d, 7H), 1.98 − 1.93 (m, acid tert-butyl 2H), 1.83 − 1.75 (m, 2H), ester 1.75 − 1.65 (m, 2H), 1.39 (d, 8H), 1.38 − 1.29 (m, 5H). SC_1347 CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSO): δ 7.36 − 444.3 (Cyclopropyl- (methylamino)- 7.32 (m, 4H), 7.26 − 7.23 (m, methyl)-8- ethanol 1H), 4.83 − 4.63 (m, 1H), dimethylamino-2- 3.99 − 3.91 (m, 2H), 3.50 − oxo-8-phenyl-1,3- 3.44 (m, 2H), 3.32 − 3.28 (m, diazaspiro[4.5]decan- 2H), 3.22 − 3.20 (m, 2H), 3-yl]-N-(2- 2.95 − 2.92 (m, 3H), 2.79 (s, hydroxy-ethyl)-N- 2H), 2.67 − 2.65 (m, 2H), methyl-acetamide 2.20 − 2.15 (m, 2H), 1.97(s, 6H), 1.42 − 1.30 (m, 4H), 0.93 − 0.90 (s, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1348 CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSO): δ 8.05 − 491.3 (Cyclopropyl- (methyl 8.02 (m, 1H), 7.37 − 7.32 (m, methyl)-8- sulfonyl)ethan- 4H), 7.26 − 7.22 (m, 1H), dimethylamino-2- amine 3.67 (s, 2H), 3.49 − 3.44 (m, oxo-8-phenyl-1,3- 2H), 3.25 − 3.21 (m, 4H), diazaspiro[4.5]decan- 2.98 − 2.93 (m, 5H), 2.67 − 3-yl]-N-(2- 2.64 (m, 2H), 2.19 − 2.13 (m, methylsulfonyl- 2H), 1.97 (s, 6H), 1.45 − 1.31 ethyl)-acetamide (m, 4H), 0.95 − 0.91 (s, 1H), 0.48 − 0.44 (m, 2H), 0.28 − 0.24 (m, 2H). SC_1349 CIS-N- INT-1032 2- SC_1308 1H NMR (600 MHz, 488.3 (Carbamoyl- methylamino- DMSO) δ 7.39 (td, 1H), methyl)-2-[1- acetamide 7.31 (s, 1H), 7.19 − 7.05 (cyclobutyl- hydrochloride (m, 3H), 6.99 (s, 1H), methyl)-8- 4.00 − 3.78 (m, 4H), 3.18 dimethylamino-8- (d, 2H), 3.07 − 3.02 (m, 2H), (3-fluorophenyl)- 2.94 (s, 2H), 2.76 (s, 1H), 2-oxo-1,3- 2.66 − 2.59 (m, 2H), 2.06 − diazaspiro[4.5]decan- 1.93 (m, 9H), 1.84 − 1.73 3-yl]-N- (m, 2H), 1.70 (dt, 2H), methyl-acetamide 1.43 − 1.28 (m, 4H) (mixture of amide rotamers) SC_1350 CIS-1-[2-[8- INT-1019 piperidine-4- SC_1308 1H NMR (DMSO d6): δ 526.4 Dimethylamino-1- carboxamide 7.37 − 7.25 (m, 6H), 6.77 (s, [(1-hydroxy- 1H), 6.02 (s, 1H), 4.26 − 4.23 cyclobutyl)- (m, 1H), 4.02 − 3.91 (m, 2H), methyl]-2-oxo-8- 3.79 − 3.75 (m, 1H), 3.31 (m, phenyl-1,3- 2H), 3.10 (s, 2H), 3.00 − 2.93 diazaspiro[4.5]decan- (t, 1H), 2.68 − 2.65 (m, 2H), 3-yl]-acetyl]- 2.60 − 2.58 (m, 2H), 2.32 − piperidine-4- 2.27 (m, 2H), 2.06 − 2.03 (m, carboxylic acid 4H), 1.91 − 1.83 (m, 8H), amide 1.67 − 1.61 (m, 2H), 1.49 − 1.40 (m, 2H), 1.36 − 1.30 (m, 4H). SC_1351 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 561.3 Dimethylamino-1- (methyl- 7.37 − 7.23 (m, 5H), 6.00 (s, [(1-hydroxy- sulfonyl)piper- 1H), 4.45 − 4.41 (m, 1H), cyclobutyl)- idine 4.08 − 3.91 (m, 3H), 3.17 (s, methyl]-3-[2-(4- 3H), 3.10 − 2.99 (m, 2H), methylsulfonyl- 2.92 (s, 3H), 2.73 − 2.65 (m, piperidin-1-yl)-2- 3H), 2.06 − 1.83 (m, 15H), oxo-ethyl]-8- 1.64 − 1.46 (m, 4H), 1.40 − phenyl-1,3- 1.30 (m, 4H). diazaspiro[4.5]decan- 2-one SC_1352 CIS-2-[1- INT-1032 2- SC_1308 1H NMR (600 MHz, 461.3 (Cyclobutyl- aminoethanol DMSO) δ 7.73 (t, 1H), 7.39 methyl)-8- (td, 1H), 7.19 − 7.05 (m, dimethylamino-8- 3H), 4.66 (t, 1H), 3.67 (s, (3-fluorophenyl)- 2H), 3.43 − 3.35 (m, 2H), 2-oxo-1,3- 3.18 (s, 2H), 3.11 (q, 2H), diazaspiro[4.5]decan- 3.05 (d, 2H), 2.65 − 2.58 3-yl]-N-(2- (m, 2H), 2.55 − 2.45 (m, hydroxy-ethyl)- 1H), 2.07 − 1.93 (m, 10H), acetamide 1.84 − 1.73 (m, 2H), 1.74 − 1.64 (m, 2H), 1.41 − 1.29 (m, 4H). SC_1353 TRANS-2-[1- INT-1067 2- SC_1357 1HNMR at 100oC. (DMSO- 443.1 (Cyclobutyl- aminoethanol d6, 400 MHz), δ (ppm) = methyl)-8- 7.44 − 7.38 (m, 5H), 7.29 (t, dimethylamino-2- 1H, J = 6.48 Hz), 4.29 (bs, oxo-8-phenyl-1,3- 1H), 3.69 (s, 2H), 3.48 − 3.44 diazaspiro[4.5]decan- (m, 2H), 3.28 (s, 2H), 3.21 − 3-yl]-N-(2- 3.17 (m, 2H), 2.69 − 2.67 (m, hydroxy-ethyl)- 2H), 2.58 − 2.55 (d, 2H, J = acetamide 11.6 Hz), 2.19 − 2.12 (m, 1H), 1.98 (s, 6H), 1.82 − 1.74 (m, 2H), 1.71 − 1.60 (m, 4H), 1.58 − 1.46 (m, 6H). SC_1354 TRANS-N- INT-1067 2- SC_1357 1HNMR at 100oC. (DMSO- 470.4 (Carbamoyl- methylamino- d6, 400 MHz), δ (ppm) = methyl)-2-[1- acetamide 7.40 − 7.28 (m, 5H), 6.87 (bs, (cyclobutyl- hydrochloride 2H), 3.94 − 3.90 (m, 4H), methyl)-8- 3.29 (s, 2H), 3.68 − 3.66 (m, dimethylamino-2- 2H), 2.58 − 2.55 (m, 2H), oxo-8-phenyl-1,3- 2.15 − 2.13 (m, 1H), 1.98 (s, diazaspiro[4.5]decan- 6H), 1.77 (bs, 2H), 1.64 − 3-yl]-N-methyl- 1.61 (m, 4H), 1.46 − 1.27 (m, acetamide 6H). SC_1355 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 513.4 Dimethylamino-1- methylpiperidin- 7.36 − 7.32 (m, 4H), 7.26 − [(1-hydroxy- 4-ol 7.23 (m, 1H), 6.02 (s, 1H), cyclobutyl)- 4.37 (s, 1H), 3.96 − 3.95 (m, methyl]-3-[2-(4- 2H), 3.90 − 3.80 (m, 1H), hydroxy-4- 3.50 − 3.40 (m, 1H), 3.30 (m, methyl-piperidin- 1H), 3.10 (s, 2H), 3.00 − 2.93 1-yl)-2-oxo- (m, 1H), 2.68 − 2.65 (m, 2H), ethyl]-8-phenyl- 2.09 − 2.04 (m, 4H), 1.97 (s, 1,3- 6H), 1.90 − 1.86 (m, 2H), diazaspiro[4.5]decan- 1.64 − 1.61 (m, 1H), 1.48 − 2-one 1.40 (m, 5H), 1.37 − 1.30 (m, 4H), 1.22 (m, 2H), 1.11 (s, 3H). SC_1356 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 461.3 (Cyclobutyl- aminoethanol DMSO) δ 7.72 (t, 1H), methyl)-8- 7.40 − 7.33 (m, 2H), 7.15 dimethylamino-8- (t 2H), 4.81 (tdd, 0.15H), 4.65 (4-fluorophenyl)- (ddq, 0.75H), 3.66 (s, 2H), 2-oxo-1,3- 3.48 (q), 3.25 (q), 3.17 (s, diazaspiro[4.5]decan- 2H), 3.11 (q, 2H), 3.05 (d, 3-yl]-N-(2- 2H), 2.66 − 2.60 (m, 2H), hydroxy-ethyl)-acetamide 2.57 − 2.47 (m, 1H), 2.06 − 1.92 (m, 10H), 1.85 − 1.73 (m, 2H), 1.75 − 1.63 (m, 2H), 1.40 − 1.28 (m, 4H). Not all signals could be intergrated due to overlap with solvent peaks; two rotamers observed in spectrum. SC_1357 TRANS-1- INT-1062 morpholine procedure 1HNMR (DMSO-d6, 400 455.1 (Cyclopropyl- described MHz), δ (ppm) = 7.44 − 7.29 methyl)-8- (m, 5H), 3.96 (s, 2H), 3.56 dimethylamino-3- (bs, 4H), 3.42 − 3.40 (m, 4H), (2-morpholin-4- 3.29 (s, 2H), 2.67 (bs, 2H), yl-2-oxo-ethyl)-8- 2.55 − 2.54 (d, 2H, J = 6.36 phenyl-1,3- Hz), 1.92 (s, 6H), 1.56 − .144 diazaspiro[4.5]decan- (m, 6H), 0.51 − 0.48 (m, 2-one 1H), 0.16 − 0.14 (m, 2H), (−0.26) − (−0.27) (m, 2H). SC_1358 TRANS-8- INT-1060 morpholine SC_1357 1HNMR (DMSO-d6, 400 401.3 Dimethylamino-3- MHz at 100 0C.), δ (ppm) = (2-morpholin-4- 7.39 − 7.36 (m, 4H), 7.26 − yl-2-oxo-ethyl)-8- 7.23 (m, 1H), 6.35 (m, 1H), phenyl-1,3- 3.91 (s, 2H), 3.59 (t, 4H, J = diazaspiro[4.5]decan- 4.8 Hz), 3.45 (t, 4H, J = 4.8 2-one Hz), 3.27 (s, 2H), 2.18 − 2.15 (m, 2H), 2.0 − 1.99 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H). SC_1359 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 475.3 (Cyclobutyl- (methyl- DMSO) δ 7.37 (dd, 2H), methyl)-8- amino)ethanol 7.15 (t, 2H), 4.82 (t, 0.2H), dimethylamino-8- 4.63 (t, 0.2H), 3.98 (s, 1H), (4-fluorophenyl)- 3.91 (s, 1H), 3.51 (q, 1H), 2-oxo-1,3- 3.45 (q, 1H), 3.37 − 3.26 diazaspiro[4.5]decan- (m, 2H), 3.18 (d, 2H), 3.04 3-yl]-N-(2- (dd, 2H), 2.96 (s, 1H), 2.80 hydroxy-ethyl)-N- (s, 2H), 2.64 (d, 2H), 2.56 − methyl-acetamide 2.47 (m, 1H), 2.08 − 2.00 (m, 2H), 2.00 − 1.91 (m, 8H), 1.79 (ddt, 2H), 1.75 − 1.65 (m, 2H), 1.37 (d, 2H), 1.31 (td, 2H). Two rotamers are observed. SC_1360 CIS-N- INT-1058 2- SC_1308 1H NMR (600 MHz, 488.3 (Carbamoyl- methylamino- DMSO) δ 7.46 (s, 0.4H), methyl)-2-[1- acetamide 7.37 (dd, 2H), 7.30 (s, (cyclobutyl- hydrochloride 0.6H), 7.20 − 7.12 (m, 2H), methyl)-8- 6.99 (s, 0.6H), 3.97 (s, 1H), dimethylamino-8- 3.90 (s, 1H), 3.83 (d, 2H), (4-fluorophenyl)- 3.18 (d, 2H), 3.04 (dd, 2H), 2-oxo-1,3- 2.94 (s, 2H), 2.76 (s, 1H), diazaspiro[4.5]decan- 2.67 − 2.60 (m, 2H), 2.57 − 3-yl]-N- 2.47 (m, 1H), 2.07 − 1.92 methyl-acetamide (m, 10H), 1.83 − 1.74 (m, 2H), 1.74 − 1.63 (m, 2H), 1.40 − 1.27 (m, 4H). Two rotamers are observed. SC_1361 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 483.4 (Cyclopropyl- hydro- methyl- 7.36 − 7.33 (m, 4H), 7.25 − methyl)-8- chloride piperidin-4-ol 7.23 (m, 1H), 4.37 (s, 1H), dimethylamino-3- 3.92 − 3.84 (m, 3H), 3.48 − [2-(4-hydroxy-4- 3.46 (m, 1H), 3.25 − 3.21 (m, methyl-piperidin- 3H), 2.99 − 2.92 (m, 3H), 1-yl)-2-oxo- 2.67 − 2.64 (m, 2H), 2.20 − ethyl]-8-phenyl- 2.15 (t, 2H), 1.97 (s, 6H), 1,3- 1.44 − 1.21 (m, 8H), 1.11 (s, diazaspiro[4.5]decan- 3H), 0.93 − 0.92 (m, 1H), 2-one 0.47 − 0.45 (m, 2H), 0.44 − 0.43 (m, 2H). SC_1362 CIS-1-[2-[1- INT-991 piperidine-4- SC_1308 1H NMR (DMSO): δ 7.34 − 496.4 (Cyclopropyl- hydro- carboxamide 7.32 (m, 4H), 7.25 − 7.24 (m, methyl)-8- chloride 2H), 6.77 (s, 1H), 4.21 − 4.29 dimethylamino-2- (m, 1H), 3.94 − 3.86 (m, 2H), oxo-8-phenyl-1,3- 3.78 (m, 1H), 3.22 (s, 2H), diazaspiro[4.5]decan- 2.96 − 2.93 (m, 3H), 2.67 − 3-yl]-acetyl]- 2.57 (m, 2H), 2.50 (t, 1H), piperidine-4- 2.30 (m, 1H), 2.20 − 2.15 (m, carboxylic acid 2H), 1.97 (s, 6H), 1.69 − 1.67 amide (m, 2H), 1.42 − 1.31 (m, 6H), 0.92 (m, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.24 (m, 2H). SC_1363 TRANS-2-[1- INT-1061 t-butyl- procedure 1HNMR at 100oC. (DMSO- 385.2 (Cyclopropyl- bromoacetate described d6, 400 MHz), δ (ppm) = methyl)-8- (step 1), 7 N 7.40 − 7.29 (m, 5H), 6.76 (bs, dimethylamino-2- ammonia in 2H), 3.68 (s, 2H), 3.33 (s, oxo-8-phenyl-1,3- methanol 2H), 2.61 − 2.60 (m, 4H), diazaspiro[4.5]decan- (step 2) 2.00 (s, 6H), 1.61 − .153 (m, 3-y]- 6H), 0.58 − 0.56 (m, 1H), acetamide 0.22 − 0.20 (m, 2H), (−0.16) − (−0.18) (m, 2H). SC_1364 TRANS-2-[1- INT-1062 methylamine SC_1357 1HNMR at 100oC. (DMSO- 399.2 (Cyclopropyl- d6, 400 MHz), δ (ppm) = methyl)-8- 7.43 − 7.27 (m, 6H), 3.68 (s, dimethylamino-2- 2H), 3.32 (s, 2H), 2.64 − 2.58 oxo-8-phenyl-1,3- (m, 7H), 1.99 (s, 6H), 1.66 − diazaspiro[4.5]decan- .152 (m, 6H), 0.58 − 0.56 (m, 3-yl]-N- 1H), 0.23 − 0.19 (m, 2H), methyl-acetamide (−0.15) − (−0.17) (m, 2H). SC_1365 TRANS-1- INT-1062 1,4-thiazinane SC_1357 1HNMR at 100oC. (DMSO- 503.3 (Cyclopropyl- 1,1-dioxide d6, 400 MHz), δ (ppm) = methyl)-8- 7.40 − 7.28 (m, 5H), 4.06 (s, dimethylamino-3- 2H), 3.90 − 3.88 (m, 4H), [2-(1,1-dioxo- 3.34 (s, 2H), 3.14 (bs, 4H), [1,4]thiazinan-4- 2.66 − 2.60 (m, 4H), 1.99 (s, yl)-2-oxo-ethyl]- 6H), 1.63 − .152 (m, 6H), 8-phenyl-1,3- 0.58-0.56 (m, 1H), 0.23 − diazaspiro[4.5]decan- 0.20 (m, 2H), (−0.16) − 2-one (−0.17) (m, 2H). SC_1366 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 531.4 (Cyclopropyl- hydro- (methyl 7.36 − 7.32 (m, 4H), 7.26 − methyl)-8- chloride sulfonyl)piper- 7.23 (m, 1H), 4.40 (m, 1H), dimethylamino-3- idine 4.04 − 3.88 (m, 3H), 3.31 (m, [2-(4- 1H), 3.02 (s, 2H), 2.94 (t, methylsulfonyl- 1H), 2.94 − 2.92 (m, 5H), piperidin-l-yl)-2- 2.67 − 2.50 (m, 3H), 2.20 − oxo-ethyl]-8- 2.15 (m, 2H), 2.08 − 1.97 (m, phenyl-1,3- 8H), 1.56 (m, 1H), 1.42 − diazaspiro[4.5]decan- 1.31 (m, 5H), 0.92 (m, 1H), 2-one 0.47 − 0.43 (m, 2H), 0.27 − 0.24 (m, 2H). SC_1368 CIS-8- INT-1019 1,4-thiazinane SC_1308 1H NMR (600 MHz, 533.3 Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (d, 4H), [2-(1,1-dioxo- 7.29 − 7.22 (m, 1H), 4.09 (s, [1,4]thiazinan-4- 2H), 3.83 (dt, 4H), 3.25 − yl)-2-oxo-ethyl]- 3.19 (m, 2H), 3.15 − 3.05 1-[(1-hydroxy- (m, 4H), 2.72 − 2.65 (m, cyclobutyl)- 2H), 2.12 − 2.04 (m, 6H), methyl]-8-phenyl- 1.99 (s, 6H), 1.88 (dt, 2H), 1,3- 1.68 − 1.59 (m, 1H), 1.50 diazaspiro[4.5]decan- (d, 2H), 1.43 − 1.29 (m, 2-one 3H). SC_1369 TRANS-2-(8- INT-1060 t-butyl- SC_1363 1HNMR (DMSO-d6, 400 331.2 Dimethylamino-2- bromoacetate MHz at 100 0C.), δ (ppm) = oxo-8-phenyl-1,3- (step 1), 7 N 7.37 − 7.24 (m, 5H), 6.74 (bs, diazaspiro[4.5]decan- ammonia in 2H), 6.38 (s, 1H), 3.62 (s, 3-yl)-acetamide methanol 2H), 3.27 (s, 2H), 2.19 − 2.14 (step 2) (m, 2H), 2.01 − 1.96 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H). SC_1370 TRANS-8- INT-1060 1,4-thiazinane SC_1357 1HNMR (DMSO-d6, 400 449.2 Dimethylamino-3- 1,1-dioxide MHz at 100 0C.), δ (ppm) = [2-(1,1-dioxo- 7.37 − 7.24 (m, 5H), 6.41 (s, [1,4]thiazinan-4- 1H), 4.0 (s, 2H), 3.89 (bs, yl)-2-oxo-ethyl]- 4H), 3.28 (s, 2H), 3.14 (bs, 8-phenyl-1,3- 4H), 2.15 (m, 2H), 1.99 (m, diazaspiro[4.5]decan- 8H), 1.78 − 1.73 (m, 2H), 2-one 1.48 − 1.43 (m, 2H). SC_1371 CIS-8- INT-1068 t-butyl- SC_1363 413.2 (dimethylamino)- bromoacetate 8-phenyl-1-(2,2,2- (step 1), 7 N trifluoroethyl)-3- ammonia in (2- methanol (trifluoro- (step 2) methyl)pyrimidin- 5-yl)-1,3- diazaspiro[4.5]decan- 2-one SC_1372 CIS-8- INT-1070 t-butyl- SC_1363 (dimethylamino)- bromoacetate 8-phenyl-3-(2- (step 1), 7 N (trifluoro- ammonia in methyl)pyrimidin- methanol 5-yl)-1-(3,3,3- (step 2) trifluoropropyl)- 1,3- diazaspiro[4.5]decan- 2-one

Chemical Structure of All Examples

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), human kappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS—HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co., St. Louis, Mo.). The final assay volume (250 μl/well) included 1 nM of [N-allyl-2,3-³H]naloxone as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 25 μM unlabelled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [³H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of 250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either test compound in dilution series or 100 μM unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [³H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and K, values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The final assay volume (250 μl/well) includes 1 nM of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 μM unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specific receptor binding are calculated by nonlinear regression analysis and K_(i) values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl, 10 mM MgCl₂, 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well) included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 1 μM unlabelled nociceptin for determination of unspecific binding. The test compound was diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [³H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

hNOP hMOP Example Ki [nM] Ki [nM] SC_1001 33 206 SC_1002 2.1 160 SC_1003 3.7 102 SC_1004 3.6 84 SC_1005 6.3 115.5 SC_1006 2.2 150 SC_1007 29.5 190 SC_1008 5.4 117.5 SC_1009 17 390 SC_1010 9.8 175 SC_1011 9.1 112.5 SC_1012 1.8 47.5 SC_1013 1 220 SC_1014 2.6 175 SC_1015 1.3 140 SC_1016 3.1 76.5 SC_1017 2.6 130 SC_1018 2.8 106.5 SC_1019 4.6 170 SC_1020 2 86 SC_1021 1.6 94 SC_1022 2.1 20.5 SC_1023 13 270 SC_1024 3.7 26.5 SC_1025 22 125 SC_1026 2 67.3 SC_1027 7.6 55 SC_1028 4.8 104 SC_1029 52.3 303.3 SC_1030 3.1 74.5 SC_1031 3.6 43 SC_1032 4.9 69.5 SC_1033 3.9 75.5 SC_1034 2.1 47 SC_1035 1.3 21.5 SC_1036 2.7 39 SC_1037 1.8 45 SC_1038 1.6 41.5 SC_1039 1.3 34.5 SC_1040 1.1 15 SC_1041 1.7 20.5 SC_1042 1.8 57 SC_1043 1.1 21.5 SC_1044 1.7 43 SC_1045 1.6 44.5 SC_1046 2.3 54 SC_1047 2.5 49 SC_1048 1 43.5 SC_1049 2.9 48.5 SC_1050 0.8 40 SC_1051 1.6 36.5 SC_1052 1.6 24.5 SC_1053 2.7 53 SC_1054 2.6 74.5 SC_1055 2.5 29 SC_1056 3.3 10 SC_1057 1.9 11 SC_1058 2.9 78 SC_1059 7.4 45 SC_1060 5.1 40.5 SC_1061 2.2 12.6 SC_1062 2.6 47.5 SC_1063 1.6 22 SC_1064 4.2 33 SC_1065 4.8 26.5 SC_1066 1.9 23 SC_1067 7.5 31.5 SC_1068 68.5 360 SC_1069 1.4 16.5 SC_1070 1 13.5 SC_1071 3.6 38.5 SC_1072 2.8 62 SC_1073 3.5 25 SC_1074 5.9 37 SC_1075 1.5 19.5 SC_1076 0.8 72 SC_1077 1.8 20.5 SC_1078 1.3 23.3 SC_1079 1.7 26.2 SC_1080 6.4 19.5 SC_1081 1.9 64 SC_1082 1 81.5 SC_1083 1.5 44 SC_1084 1.1 59 SC_1085 3.8 71 SC_1086 0.8 16.5 SC_1087 2.4 28.2 SC_1088 2 19.5 SC_1089 1.4 16.5 SC_1090 3 27.5 SC_1091 1.3 15.5 SC_1092 1.8 26.5 SC_1093 4.2 43 SC_1094 2.8 10.4 SC_1095 1.8 12.5 SC_1096 1.6 12 SC_1097 1.6 15 SC_1098 1.5 10 SC_1099 1.5 4.5 SC_1100 1 2.3 SC_1101 3.4 6 SC_1102 2 4.4 SC_1103 0.4 7.2 SC_1104 1.2 23 SC_1105 4 50.5 SC_1106 11 122 SC_1107 1.8 45 SC_1109 2.8 16 SC_1110 9.8 31.5 SC_1111 1.6 30 SC_1112 1.3 30.5 SC_1113 0.8 30 SC_1114 109.5 850 SC_1115 140 145 SC_1117 4.1 37.5 SC_1118 2.4 114.3 SC_1119 6.5 73.5 SC_1120 2.9 125 SC_1121 115 630 SC_1122 124.5 480 SC_1123 2.6 24.8 SC_1124 1.8 33.8 SC_1125 2.2 23 SC_1126 3.5 29.5 SC_1127 2.6 2.7 SC_1128 1.9 72 SC_1129 1.7 37.3 SC_1130 68.5 160 SC_1131 34.5 215 SC_1132 23.5 410 SC_1133 6.4 25.5 SC_1134 26 140 SC_1135 73 370 SC_1136 14 57.5 SC_1137 5.8 99 SC_1138 0.9 23.5 SC_1139 215 515 SC_1140 51.5 150 SC_1141 4.8 165 SC_1142 265 1200 SC_1143 17 200 SC_1144 9.8 73.5 SC_1145 3.4 60.5 SC_1146 2.2 21.2 SC_1147 2.6 34.2 SC_1148 40 18.8 SC_1149 62 102.5 SC_1150 4.9 55.5 SC_1151 1.6 13.5 SC_1152 0.9 13.7 SC_1153 1.6 37 SC_1154 4.5 29 SC_1155 14.1 114.5 SC_1156 155 1215 SC_1157 170 1120 SC_1158 12.5 144.5 SC_1159 22.5 81.5 SC_1160 20 84.5 SC_1161 60 86 SC_1162 15.3 47.5 SC_1163 30.5 119 SC_1164 8.2 16.5 SC_1165 5.7 63.5 SC_1166 17 72.5 SC_1167 18 92 SC_1168 37 125 SC_1169 36.5 370 SC_1171 43 130 SC_1172 27.5 106 SC_1173 38.5 120 SC_1174 12.9 195 SC_1175 28.5 9.6 SC_1176 9 56 SC_1177 39 660 SC_1178 16 390 SC_1179 87.5 180 SC_1180 80 230 SC_1181 125 435 SC_1182 47.5 320 SC_1183 130 185 SC_1184 110 153.3 SC_1185 47 165 SC_1186 95.5 355 SC_1187 43 127.5 SC_1188 9.1 175 SC_1189 70.5 75.5 SC_1190 11.2 123.5 SC_1191 29 150 SC_1192 17 680 SC_1193 9.9 41 SC_1195 4.4 6.2 SC_1196 2.1 64.8 SC_1197 5.4 60 SC_1198 4.9 47 SC_1199 35 230 SC_1201 13.3 123.7 SC_1203 5.2 47.5 SC_1204 2.5 77.2 SC_1205 2.2 37 SC_1206 1.2 61.5 SC_1207 2.9 38 SC_1208 1.8 90 SC_1209 3.2 46 SC_1210 4.4 83.5 SC_1211 2.4 18.7 SC_1212 4.8 37.7 SC_1213 1.8 31.7 SC_1214 1 56.7 SC_1215 3.9 25 SC_1216 1.2 49 SC_1217 2.2 25.7 SC_1218 5.2 59 SC_1219 4.2 73.7 SC_1220 4 51 SC_1221 17 180 SC_1222 2.6 63 SC_1223 2.5 43.5 SC_1224 1.6 15 SC_1225 1.8 49.5 SC_1226 2.6 12.5 SC_1227 4.6 63 SC_1228 665 1740 SC_1229 2.8 22.5 SC_1230 1.5 36.5 SC_1231 2 51.5 SC_1232 1.4 32.5 SC_1233 0.5 26.5 SC_1234 1.8 53.5 SC_1236 3.3 83 SC_1300 13 130 SC_1301 23 44 SC_1302 27 66.5 SC_1303 145 215 SC_1304 280 400 SC_1305 19 105.5 SC_1306 59 45 SC_1308 22 97 SC_1309 12.5 100 SC_1310 8.1 17 SC_1311 11.5 44 SC_1312 295 520 SC_1313 305 1015 SC_1317 1.4 53.5 SC_1318 89 960 SC_1319 4 71 SC_1320 4 51 SC_1321 17 180 SC_1322 6%@1 μM 9%@1 μM SC_1323 12%@1 μM 7%@1 μM SC_1324 330 6025 SC_1325 0%@1 μM 5%@1 μM SC_1326 0%@1 μM 625 SC_1327 11 120 SC_1328 2%@1 μM 6%@1 μM SC_1329 0%@1 μM 4%@1 μM SC_1330 465 18%@1 μM SC_1331 10 38 SC_1332 52 1950 SC_1333 36 300 SC_1334 195 1605 SC_1335 2 24 SC_1336 — — SC_1337 23 — SC_1338 475 14%@1 μM SC_1339 1110 9%@1 μM SC_1340 230 14%@1 μM SC_1341 170 2905 SC_1342 1140 10%@1 μM SC_1343 12 95 SC_1344 13 145 SC_1345 1 185 SC_1346 2 400 SC_1347 31 615 SC_1348 8 97 SC_1349 1 165 SC_1350 8 510 SC_1351 1 235 SC_1352 1 135 SC_1353 66 80.5 SC_1354 465 210 SC_1355 7 325 SC_1356 11 86 SC_1357 100 15.5 SC_1358 73 51.5 SC_1359 10 260 SC_1360 15 180 SC_1361 13 255 SC_1362 6 240 SC_1363 185 225 SC_1364 230 73.5 SC_1365 160 4.4 SC_1366 1 205 SC_1368 7 360 SC_1369 465 1805 SC_1370 100 11

Protocol for [³⁵S]G-TPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [³⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane protein per assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃, and 10 μM GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads. The microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TB_(obs) [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC₅₀) of the respective agonist and its maximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculated basal binding (UBS_(calc) [%]) are determined from its transformed data (TB_(obs) [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and the maximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by each tested agonist is determined (i.e. B1_(calc) [%]). This difference (B1_(calc) [%]) as a measure of the maximal achievable enhancement of [³⁵S]GTPγS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) DAMGO (B1_(calc-DAMGO) [%]) and U69,593 (B1_(calc-U69,593) [%]) which are set as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof. 

1. A compound according to general formula (I) wherein

R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, -OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; X means —O—, —S— or —NR⁶—; R⁵ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; in case X means NR⁶, R⁶ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H, —O—, (CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —S(═O)R²¹, —S (═O)₂R²¹, —S(═O)₂OR²¹, and —S (═O)₂NR²¹R²²; wherein R²¹, R²² and R²³ independently of one another mean —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═)NR²¹R²², or —S(═O)₂NR²¹R²² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; or a physiologically acceptable salt thereof.
 2. The compound according to claim 1, wherein R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl.
 3. The compound according to claim 1, wherein R¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 4. The compound according to claim 1, wherein R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 5. The compound according to claim 1, wherein R¹ means —H or —CH₃; and wherein R² means —CH₂-cycloalkyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-oxetanyl or —CH₂-tetrahydrofuranyl.
 6. The compound according to claim 1, wherein R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—.
 7. The compound according to claim 1, wherein R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 8. The compound according to claim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
 9. The compound according to claim 1, wherein R³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
 10. The compound according to claim 1, wherein R⁴ means —H.
 11. The compound according to claim 1, wherein R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 12. The compound according to claim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 13. The compound according to claim 1, wherein R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 14. The compound according to claim 1, wherein R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 15. The compound according to claim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 16. The compound according to claim 1, wherein R⁵ means —H.
 17. The compound according to claim 1, wherein R⁵ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 18. The compound according to claim 1, wherein R⁵ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 19. The compound according to claim 1, wherein R⁵ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 20. The compound according to claim 1, wherein R⁵ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 21. The compound according to claim 1, wherein X means NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 22. The compound according to claim 1, wherein X means NR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 23. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, R⁵, R⁶ and X are defined as in claim 1, R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means —H or —F; or a physiologically acceptable salt thereof.
 24. The compound according to claim 1, wherein the substructure

has a meaning selected from the group consisting of:


25. The compound according to claim 1, wherein R¹ means —H or —CH₃; R² means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂; R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or monosubstituted with —F; R⁴ means —H; —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —N(CH₃)₂ and —O—CH₃; or -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH₂— or —CH₂CH₂—; -oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein said -oxetanyl is connected through —CH₂— or —CH₂CH₂—; X means —O— or —NR⁶—; R⁵ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H, —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OH, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃; -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH₂— or —CH₂CH₂—; -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H, —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH, —SCH₃, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃; wherein said -hetero-cyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is optionally connected through —CH₂— or —CH₂CH₂—; -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally connected through —CH₂—; or -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, wherein said -phenyl is optionally connected through —CH₂—; in case X means NR⁶, R⁶ means —H or —CH₃; or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to which they are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of =O, —OH, —CH₂—OH, —C(═O)NH₂, and —S(═O)₂CH₃, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted; and R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.
 26. The compound according to claim 1, which has a structure according to general formula (I′)

wherein R¹ to R⁵, R⁹ to R²⁰, and X are defined as in claim 1, or a physiologically acceptable salt thereof.
 27. The compound according to claim 1, which has a structure according to general formula (IX)

wherein R^(C) means —H or —OH; R³ means -phenyl or -3-fluorophenyl; R⁵ means —H, —CH₃, —CH₂CH₂OH, or —CH₂C(═O)NH₂; R⁶ means —H or —CH₃; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₅—, wherein said ring is unsubstituted or substituted with one or two substituents independently of one another selected from the group consisting of —CH₃, —OH, —S(═O)₂CH₃ and —C(═O)NH₂; R⁹ and R¹⁰ independently of one another mean —H or —CH₃; or a physiologically acceptable salt thereof.
 28. The compound according to claim 1, which is selected from the group consisting of CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide; CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide; CIS-2-[1-Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide; CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide; CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide; CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid amide; CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide; CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[1-methyl-1H-imidazol-4-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide; CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid amide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide; CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide; CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[[2-[8-Dimethylamino-1-[1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide; CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide; CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[1,1-dioxo-thian-4-yl)-methyl]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide; CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide; CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide; CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione; CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide; CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide; TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide; CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide; TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide; TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide; TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide; TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one and the physiologically acceptable salts thereof.
 29. The compound according to claim 1 adapted for use in the treatment of pain.
 30. A medicament comprising a compound according to claim
 1. 31. A method of treating pain in a patient in need thereof, said method comprising administering to said patient an effective amount therefor of at least one compound according to claim
 1. 32. A method of treating a disorder selected from the group consisting of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence, said method comprising administering to a patient in need thereof an effective amount therefor of at least one compound according to claim
 1. 